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THE PHARMACOLOGICAL BASIS OF
THERAPEUTICS
FOURTEENTH EDITION
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THE PHARMACOLOGICAL BASIS OF
THERAPEUTICS
FOURTEENTH EDITION
Editor-in-Chief
Laurence L. Brunton, PhD
Professor of Pharmacology
School of Medicine
University of California, San Diego
La Jolla, California
Editor
Björn C. Knollmann, MD, PhD
William Stokes Professor of Medicine and Pharmacology
Fellowship Director, Division of Clinical Pharmacology
Director, Vanderbilt Center for Arrhythmia Research and
Therapeutics (VanCART)
Vanderbilt University School of Medicine
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Contents
Contributors ix 18. Drug Therapy of Depression and Anxiety Disorders..................... 343

Preface xv James M. O’Donnell, Robert R. Bies, and Aislinn J. Williams
Acknowledgments xvii 19. Pharmacotherapy of Psychosis and Mania...................................... 357
Jonathan M. Meyer
20. Pharmacotherapy of the Epilepsies................................................... 385
Section I Cameron S. Metcalf, Misty D. Smith, and Karen S. Wilcox
General Principles 1 21. Treatment of Central Nervous System
1. Drug Discovery: From Medicinal Plants to Computer-Aided Degenerative Disorders...................................................................... 413
Drug Design ............................................................................................ 3 Erik D. Roberson and Talene A. Yacoubian
Michael K. Gilson and Laurence L. Brunton 22. Hypnotics and Sedatives.................................................................... 427
2. Pharmacokinetics: The Dynamics of Drug Absorption, S. John Mihic and Jody Mayfield
Distribution, Metabolism, and Elimination...................................... 23 23. Opioid Analgesics .............................................................................. 443
Iain L. O. Buxton Emily M. Jutkiewicz and John R. Traynor
3. Pharmacodynamics: Molecular Mechanisms of Drug Action........ 43 24. General Anesthetics and Therapeutic Gases................................... 471
David R. Manning and Donald K. Blumenthal Jerry Ingrande, Matthew L. Pearn, and Hemal H. Patel
4. Membrane Transporters and Drug Response................................... 79 25. Local Anesthetics................................................................................ 489
Kathleen M. Giacomini and Yuichi Sugiyama William A. Catterall and Kenneth Mackie
5. Drug Metabolism................................................................................ 101 26. Cannabinoids....................................................................................... 505
Frank J. Gonzalez and Michael Coughtrie Matthew N. Hill and Kenneth Mackie
6. The Gastrointestinal Microbiome and Drug Response................. 119 27. Ethanol.................................................................................................. 519
Shirley M. Tsunoda, Pieter C. Dorrestein, and Rob Knight Jody Mayfield and S. John Mihic
7. Pharmacogenetics and Pharmacogenomics.................................... 131 28. Drug Use Disorders and Addiction.................................................. 531
Dan M. Roden and Sara L. Van Driest Christine Konradi and Yasmin L. Hurd
8. Postmarketing Drug Safety................................................................ 145
C. Michael Stein and Wayne A. Ray
9. Principles of Clinical Toxicology...................................................... 155
Section III
Amberly R. Johnson and Kaitlyn M. Brown Modulation of Pulmonary, Renal,
and Cardiovascular 555
Section II 29. Drugs Affecting Renal Excretory Function..................................... 557
Edwin K. Jackson
Neuropharmacology 171 30. Renin and Angiotensin....................................................................... 585
10. Neurotransmission: The Autonomic and Somatic Motor Krishna Sriram and Paul A. Insel
Nervous Systems................................................................................. 173 31. Treatment of Ischemic Heart Disease............................................... 607
Rebecca Petre Sullivan, Steven R. Houser, and Walter J. Koch
Thomas Eschenhagen
11. Muscarinic Receptor Agonists and Antagonists............................. 207 32. Treatment of Hypertension................................................................ 625
Joan Heller Brown, Katharina Brandl, and Jürgen Wess
Thomas Eschenhagen
12. Anticholinesterase Inhibitors and Reactivators.............................. 221 33. Therapy of Heart Failure.................................................................... 647
Palmer Taylor
Thomas Eschenhagen
13. Neuromuscular Junction and Autonomic Ganglia; Nicotine, 34. Antiarrhythmic Drugs........................................................................ 667
Muscle Relaxants, and Spasmolytics ................................................ 235 Bjorn C. Knollmann, Dan M. Roden, and Katherine T. Murray
Ryan E. Hibbs and Alexander C. Zambon
35. Treatment of Pulmonary Arterial Hypertension............................ 695
14. Adrenergic Agonists and Antagonists.............................................. 251 Dustin R. Fraidenburg, Ankit A. Desai, Ayako Makino,
Douglas G. Tilley, Steven R. Houser, and Walter J. Koch and Jason X.-J. Yuan
15. 5-Hydroxytryptamine (Serotonin) and Dopamine........................ 285 36. Blood Coagulation and Anticoagulant, Fibrinolytic, and
Charles D. Nichols, Susan G. Amara, and David R. Sibley
Antiplatelet Drugs............................................................................... 709
16. Neurotransmission in the Central Nervous System....................... 305 Jeffrey I. Weitz
R. Benjamin Free, Suzanne M. Underhill, Susan G. Amara,
37. Drug Therapy for Dyslipidemias...................................................... 729
and David R. Sibley
Natalia Ruiz-Negrón and Donald K. Blumenthal
17. The Blood-Brain Barrier and Its Influence on Drug
Transport to the Brain........................................................................ 327
Richard Daneman, Margareta Hammarlund-Udenaes,
and Eric V. Shusta
viii Section IV 58. Cell Envelope Disruptors: β-Lactam, Glycopeptide, and
Lipopeptide Antibacterials.............................................................. 1147
Inflammation, Immunomodulation, Conan MacDougall
and Hematopoiesis 747 59. Miscellaneous Antibacterials: Aminoglycosides, Polymyxins,
38. Introduction to Immunity and Inflammation................................. 749 Urinary Antiseptics, Bacteriophages.............................................. 1167
Michael David Conan MacDougall and Robert T. Schooley
39. Immunosuppressants, Immunomodulation, and Tolerance......... 769 60. Protein Synthesis Inhibitors ............................................................ 1179
Carla V. Rothlin and J. Silvio Gutkind Conan MacDougall
Contents
40. Immune Globulins and Vaccines...................................................... 793 61. Antifungal Agents............................................................................. 1193
Roberto Tinoco and James E. Crowe, Jr. P. David Rogers and Damian J. Krysan
41. Lipid-Derived Autacoids: Eicosanoids and 62. Antiviral Agents (Nonretroviral).................................................... 1211
Platelet-Activating Factor................................................................... 815 Edward P. Acosta
Emanuela Ricciotti, Tilo Grosser, and Garret A. FitzGerald 63. Treatment of Viral Hepatitis (HBV/HCV).................................... 1227
42. Pharmacotherapy of Inflammation, Fever, Pain, and Gout........... 829 Jennifer J. Kiser
Tilo Grosser, Emanuela Ricciotti, and Garret A. FitzGerald 64. Antiretroviral Agents and Treatment of HIV Infection............... 1245
43. Histamine, Bradykinin, and Their Antagonists.............................. 857 Charles W. Flexner
Bruce L. Zuraw and Sandra C. Christiansen 65. Chemotherapy of Tuberculosis and Nontuberculous
44. Pulmonary Pharmacology................................................................. 875 Mycobacteria, Including Leprosy ................................................... 1267
Peter J. Barnes Elisa H. Ignatius and Kelly E. Dooley
45. Hematopoietic Agents: Growth Factors, Minerals, 66. Chemotherapy of Malaria................................................................ 1289
and Vitamins........................................................................................ 899 Abdoulaye A. Djimdé and Steve M. Taylor
Michael Choi and Thomas J. Kipps 67. Chemotherapy of Protozoal Infections: Amebiasis, Giardiasis,
Trichomoniasis, Trypanosomiasis, Leishmaniasis, and Other
Protozoal Infections.......................................................................... 1309
Section V Dawn M. Wetzel and Margaret A. Phillips
Endocrine Pharmacology 921 68. Chemotherapy of Helminth Infections.......................................... 1325
46. Introduction to Endocrinology: Jennifer Keiser, James McCarthy, and Peter Hotez
The Hypothalamic-Pituitary Axis..................................................... 923
Dequina A. Nicholas and Mark A. Lawson
Section VIII
47. Thyroid and Antithyroid Drugs........................................................ 941
Ronald J. Koenig and Gregory A. Brent Pharmacotherapy of Neoplastic Disease 1335
Section Editor: Anton Wellstein
48. Estrogens, Progestins, and the Female Reproductive Tract........... 959
Ellis R. Levin, Wendy S. Vitek, and Stephen R. Hammes 69. General Principles in the Pharmacotherapy of Cancer................ 1337
49. Androgens and the Male Reproductive Tract................................. 991 Anton Wellstein
Peter J. Snyder 70. Cytotoxics and Antimetabolites...................................................... 1343
50. Adrenocorticotropic Hormone, Adrenal Steroids, Anton Wellstein and Edward A. Sausville
and the Adrenal Cortex.................................................................... 1003 71. Protein Kinase Inhibitors and Pathway-Targeted
Christopher J. Hupfeld and Jorge Iñiguez-Lluhí Small Molecules ................................................................................ 1381
51. Endocrine Pancreas and Pharmacotherapy of Anton Wellstein and Giuseppe Giaccone
Diabetes Mellitus and Hypoglycemia............................................. 1023 72. Antibodies, CAR T Cells, and Proteins to Treat Cancer.............. 1415
Alvin C. Powers and David D’Alessio Anton Wellstein and Michael B. Atkins
52. Agents Affecting Mineral Ion Homeostasis 73. Hormones, Hormone Receptor Antagonists, and
and Bone Turnover........................................................................... 1049 Related Agents in the Therapy of Cancer...................................... 1435
Thomas D. Nolin and Peter A. Friedman Claudine Isaacs, Kerry L. Burnstein, and Anna T. Riegel
Section VI Section IX
Gastrointestinal Pharmacology 1071 Special Systems Pharmacology 1451
53. Pharmacotherapy for Gastric Acidity, Peptic Ulcers, and 74. Ocular Pharmacology....................................................................... 1453
Gastroesophageal Reflux Disease................................................... 1073 Upneet K. Bains, Zeba A. Syed, Jeffrey D. Henderer,
Keith A. Sharkey and Wallace K. MacNaughton and Christopher J. Rapuano
54. Gastrointestinal Motility and Water Flux, Emesis, 75. Dermatological Pharmacology........................................................ 1475
Matthew J. Sewell and Dean S. Morrell
and Biliary and Pancreatic Disease................................................. 1085
Keith A. Sharkey and Wallace K. MacNaughton 76. Environmental Toxicology............................................................... 1507
Allison K. Ehrlich
55. Pharmacotherapy of Inflammatory Bowel Disease...................... 1111
Wallace K. MacNaughton and Keith A. Sharkey
Appendices
Section VII I. Design and Optimization of Dosage Regimens:
Pharmacokinetic Data...................................................................... 1533
Chemotherapy of Infectious Diseases 1125 Isabelle Ragueneau-Majlessi, Jingjing Yu, and Nina Isoherranen
Section Editor: Conan MacDougall
II. Drug-Drug Interactions................................................................... 1591
56. General Principles of Antimicrobial Therapy............................... 1127 Isabelle Ragueneau-Majlessi, Jingjing Yu, and Nina Isoherranen
Conan MacDougall
57. DNA Disruptors: Sulfonamides, Quinolones, Index 1595
and Nitroimidazoles ........................................................................ 1137
Conan MacDougall

Contributors
Edward Acosta, PharmD Kaitlyn Brown, PharmD, DABAT

Professor and Director, Clinical Pharmacology Clinical Supervisor
University of Alabama at Birmingham School of Medicine Adjunct Instructor–Utah Poison Control Center
Birmingham, Alabama Department of Pharmacotherapy
University of Utah College of Pharmacy
Susan G. Amara, PhD Salt Lake City, Utah
Scientific Director
National Institute of Mental Health Laurence L. Brunton, PhD
National Institutes of Health Emeritus Professor of Pharmacology
Bethesda, Maryland Department of Pharmacology, School of Medicine
Michael B. Atkins, MD La Jolla, California
Professor of Oncology and Medicine
Georgetown University School of Medicine Kerry L. Burnstein, PhD
Washington, DC Professor and Chair
Department of Molecular and Cellular Pharmacology
Upneet Kaur Bains, MD Miller School of Medicine
Assistant Professor of Ophthalmology University of Miami
Lewis Katz School of Medicine at Temple University Miami, Florida
Philadelphia, Pennsylvania
Iain L. O. Buxton, PharmD, FAHA
Peter J. Barnes, FRS, FMedSci Foundation Professor
Professor of Thoracic Medicine Department of Pharmacology
National Heart & Lung Institute University of Nevada, Reno School of Medicine
Imperial College London Reno, Nevada
London, United Kingdom
William A. Catterall, PhD
Robert R. Bies, PharmD, PhD Professor of Pharmacology
Associate Professor School of Medicine
School of Pharmacy and Pharmaceutical Sciences University of Washington
The State University of New York, Buffalo Seattle, Washington
Buffalo, New York
Michael Choi, MD
Donald K. Blumenthal, PhD Associate Clinical Professor
Associate Professor of Pharmacology Moores Cancer Center
College of Pharmacy University of California, San Diego
University of Utah La Jolla, California
Salt Lake City, Utah
Sandra Christiansen, MD
Katharina Brandl, PhD Clinical Professor of Health Sciences
Associate Professor University of California, San Diego
Skaggs School of Pharmacy and Pharmaceutical Sciences La Jolla, California
La Jolla, California Michael W. H. Coughtrie, PhD
Professor and Dean
Gregory A. Brent, MD Faculty of Pharmaceutical Sciences
Professor of Medicine and Physiology University of British Columbia
Chief, Division of Endocrinology, Diabetes and Metabolism Vancouver, Canada
David Geffen School of Medicine
University of California, Los Angeles James E. Crowe, Jr., MD
Los Angeles, California Professor of Pediatrics, Pathology, Microbiology and Immunology
Vanderbilt University Medical Center
Joan Heller Brown, PhD Nashville, Tennessee
Distinguished Professor, Emeritus Chair
Department of Pharmacology
x David D’Alessio, MD R. Benjamin Free, PhD
Professor, Department of Medicine Staff Scientist, Neuropharmacology Section
Director, Division of Endocrinology National Institute of Neurological Disorders and Stroke
Duke University Medical Center National Institutes of Health
Durham, North Carolina Bethesda, Maryland
Richard Daneman, PhD Peter A. Friedman, PhD

Associate Professor of Pharmacology and Neurosciences Professor
Contributors
University of California, San Diego Department of Pharmacology and Chemical Biology

La Jolla, California University of Pittsburgh School of Medicine
Pittsburgh, Pennsylvania
Michael David, PharmD, PhD
Professor Division of Biological Sciences and Kathleen M. Giacomini, PhD
Moores Cancer Center Professor of Bioengineering and Therapeutic Sciences
University of California, San Diego School of Pharmacy
La Jolla, California University of California, San Francisco
San Francisco, California
Ankit A. Desai, MD
Associate Professor of Medicine Giuseppe Giaconne, MD, PhD
Indiana University Professor of Medicine
Indianapolis, Indiana Associate Director of Clinical Research
Sandra and Edward Meyer Cancer Center
Abdoulaye Djimdé, PharmD, PhD Weill Cornell Medical Center
CAMES Professor of Parasitology and Mycology New York, New York
University of Science, Techniques and Technologies of Bamako
Bamako, Mali Michael K. Gilson, MD, PhD
Distinguished Professor
Kelly Dooley, MD, PhD, MPH Skaggs School of Pharmacy and Pharmaceutical Sciences
Professor of Medicine, Pharmacology & Molecular Sciences University of California, San Diego
Johns Hopkins University School of Medicine La Jolla, California
Baltimore, Maryland
Frank J. Gonzalez, PhD
Pieter C. Dorrestein, PhD Chief, Laboratory of Metabolism
Professor, Departments of Pharmacology and Pediatrics Center for Cancer Research
Skaggs School of Pharmacy & Pharmaceutical Sciences National Cancer Institute
University of California, San Diego National Institutes of Health
La Jolla, California Bethesda, Maryland
Allison K. Ehrlich, PhD Tilo Grosser, MD
Assistant Professor of Environmental Toxicology Research Associate Professor of Pharmacology
University of California, Davis Institute for Translational Medicine and Therapeutics
Davis, California University of Pennsylvania
Thomas Eschenhagen, MD Philadelphia, Pennsylvania
Professor and Chair of Pharmacology Silvio Gutkind, PhD
Department of Experimental Pharmacology and Toxicology Distinguished Professor and Chair
University Medical Center Hamburg-Eppendorf Department of Pharmacology
Hamburg, Germany University of California, San Diego
Garret A. FitzGerald, MD, FRS La Jolla, California
Director, Institute for Translational Medicine and Therapeutics Margareta Hammarlund-Udenaes, PhD
Perelman School of Medicine Professor of Pharmacokinetics and Pharmacodynamics
University of Pennsylvania Department of Pharmacy
Philadelphia, Pennsylvania Uppsala University
Charles W. Flexner, MD Uppsala, Sweden
Professor of Medicine, Pharmacology and Molecular Sciences, and Stephen R. Hammes, MD, PhD
International Health Professor of Medicine
Chief Scientific Officer, Institute for Clinical and Chief of Endocrinology and Metabolism
Translational Research School of Medicine and Dentistry
Johns Hopkins University University of Rochester
Baltimore, Maryland Rochester, New York
Dustin R. Fraidenburg, MD Jeffrey D. Henderer, MD
Assistant Professor of Medicine Professor of Ophthalmology
Director, Pulmonary Hypertension Program Dr. Edward Hagop Bedrossian Chair of Ophthalmology
University of Illinois Lewis Katz School of Medicine at Temple University
Chicago, Illinois Philadelphia, Pennsylvania

Ryan E. Hibbs, PhD Nina Isoherranen, MS, PhD xi
Associate Professor of Neuroscience Professor of Pharmaceutics
University of Texas Southwestern Medical School University of Washington School of Pharmacy
Dallas, Texas Seattle, Washington
Matthew N. Hill, PhD Edwin K. Jackson, PhD

Professor Professor of Pharmacology and Chemical Biology
Hotchkiss Brain Institute University of Pittsburgh
Contributors
Cumming School of Medicine Pittsburgh, Pennsylvania
University of Calgary
Calgary, Canada Amberly R. Johnson, PharmD, DABAT
Director, Utah Poison Control Center
Peter J. Hotez, MD, PhD Assistant Professor (Clinical)
Professor of Pediatrics and Molecular Virology and Microbiology University of Utah College of Pharmacy
Texas Children’s Hospital Endowed Chair in Tropical Pediatrics Salt Lake City, Utah
Dean, National School of Tropical Medicine
Baylor College of Medicine Emily M. Jutkiewicz, PhD
Houston, Texas Associate Professor of Pharmacology
University of Michigan
Steven R. Houser, PhD Ann Arbor, Michigan
Senior Associate Dean, Research
Vera J. Goodfriend Chair in Cardiovascular Research Jennifer Keiser, PhD
Director and Professor, Cardiovascular Research Center Associate Professor of Neglected Tropical Diseases
Professor, Cardiovascular Sciences and Medicine Unit Head
Lewis Katz School of Medicine Swiss Tropical & Public Health Institute
Temple University Allschwil, Switzerland
Philadelphia, Pennsylvania Thomas J. Kipps, MD, PhD
Christopher J. Hupfeld, MD Professor of Medicine, Moores Cancer Center
Clinical Professor of Medicine University of California, San Diego
Division of Endocrinology, School of Medicine La Jolla, California
University of California, San Diego Jennifer J. Kiser, PharmD, PhD
La Jolla, California Associate Professor
Yasmin L. Hurd, PhD Department of Pharmaceutical Sciences
Professor of Pharmacological Sciences, Neuroscience and Psychiatry University of Colorado Anschutz Medical Campus
Icahn School of Medicine at Mount Sinai Aurora, Colorado
New York, New York Rob Knight, PhD
Elisa H. Ignatius, MD, MSc Professor of Pediatrics
Assistant Professor of Medicine Affiliate Professor of Computer Science and Engineering
Division of Clinical Pharmacology and Infectious Diseases Director of the Center for Microbiome Innovation
Johns Hopkins University School of Medicine University of California, San Diego
Baltimore, Maryland La Jolla, California
Jerry Ingrande, MD, MS Bjorn C. Knollmann, MD, PhD

Associate Clinical Professor William Stokes Professor of Medicine and Pharmacology
Department of Anesthesiology, School of Medicine Fellowship Director, Division of Clinical Pharmacology
University of California, San Diego Director, Vanderbilt Center for Arrhythmia Research and
La Jolla, California Therapeutics (VanCART)
Vanderbilt University School of Medicine
Jorge Iniguez-Lluhi, PhD Nashville, Tennessee
Associate Professor of Pharmacology
University of Michigan Walter J. Koch, PhD
Ann Arbor, Michigan W.W. Smith Chair in Cardiovascular Medicine
Professor and Chair, Department of Cardiovascular Sciences
Paul A. Insel, MD Lewis Katz School of Medicine, Temple University
Distinguished Professor of Pharmacology and Medicine, Emeritus Philadelphia, Pennsylvania
Co-Director, Medical Scientist (MD/PhD) Training Program
University of California, San Diego Ronald J. Koenig, MD, PhD
La Jolla, California Professor Emeritus of Internal Medicine
Division of Metabolism, Endocrinology and Diabetes
Claudine Isaacs, MD, FRCPC University of Michigan
Professor of Medicine and Oncology Ann Arbor, Michigan
Associate Director for Clinical Research
Lombardi Comprehensive Cancer Center Christine Konradi, PhD
Georgetown University Professor of Pharmacology and Psychiatry
Washington, DC School of Medicine
Vanderbilt University
xii Damian J. Krysan, MD, PhD Jonathan M. Meyer, MD
Division Director, Pediatric Infectious Disease Psychopharmacology Consultant, California Department of
Samuel J. Fomon Chair in Pulmonology/Allergy/Infectious Diseases State Hospitals
Professor of Pediatrics and Microbiology/Immunology Assistant Clinical Professor of Psychiatry
Carver College of Medicine University of California, San Diego
University of Iowa La Jolla, California
Iowa City, Iowa
S. John Mihic, PhD
Contributors
Mark A. Lawson, PhD Associate Professor of Neuroscience

Professor of Obstetrics, Gynecology, and Reproductive Sciences University of Texas
School of Medicine Austin, Texas
La Jolla, California Dean S. Morrell, MD
Professor of Dermatology
Ellis R. Levin, MD University of North Carolina
Professor of Medicine Chapel Hill, North Carolina
Chief of Endocrinology, Diabetes and Metabolism
Veterans Affairs Long Beach Health Care System Katherine T. Murray, MD
University of California, Irvine Professor of Medicine and Pharmacology
Irvine, California Vanderbilt University School of Medicine
Conan MacDougall, PharmD, MAS
Professor of Clinical Pharmacy Dequina A. Nicholas, PhD
University of California, San Francisco Assistant Professor of Molecular Biology and Biochemistry
San Francisco, California School of Biological Sciences
University of California, Irvine
Kenneth P. Mackie, MD Irvine, California
Professor of Psychological and Brain Sciences
Director, Gill Center for Biomolecular Science Charles D. Nichols, PhD
Indiana University Professor
Bloomington, Indiana Department of Pharmacology and Experimental Therapeutics
Louisiana State University Health Sciences Center
Wallace K. MacNaughton, PhD, CAGF, FAPS New Orleans, Louisiana
Professor of Physiology and Pharmacology
University of Calgary Thomas D. Nolin, PharmD, PhD
Calgary, Canada Associate Dean for Research and Sponsored Programs
School of Pharmacy, University of Pittsburgh
Ayako Makino, PhD Pittsburgh, Pennsylvania
Associate Professor of Medicine
University of California, San Diego James M. O’Donnell, PhD
La Jolla, California Professor of Pharmaceutical Sciences
School of Pharmacy and Pharmaceutical Sciences
David R. Manning, PhD State University of New York at Buffalo
Emeritus Professor of Systems Pharmacology and Buffalo, New York
Translational Therapeutics
Perelman School of Medicine Hemal H. Patel, PhD
University of Pennsylvania Professor and Vice Chair of Research
Philadelphia, Pennsylvania Department of Anesthesiology, School of Medicine
Jody Mayfield, PhD La Jolla, California
Science Writer and Editor
Waggoner Center for Alcohol and Addiction Research Matthew L. Pearn, MD
University of Texas Associate Professor of Anesthesiology
Austin, Texas VA-San Diego Healthcare System
James McCarthy, MD La Jolla, California
Director, Victorian Infectious Diseases Service
Peter Doherty Institute Margaret A. Phillips, PhD
Royal Melbourne Hospital Professor and Chair
University of Melbourne Department of Biochemistry
Melbourne, Australia University of Texas Southwestern Medical Center
Dallas, Texas
Cameron S. Metcalf, PhD
Research Assistant Professor of Pharmacology & Toxicology Alvin C. Powers, MD
Associate Director, Epilepsy Therapy Screening Program Contract Site Joe C. Davis Chair in Biomedical Science
University of Utah Professor of Medicine, Molecular Physiology and Biophysics
Salt Lake City, Utah Director, Vanderbilt Diabetes Center
Chief, Division of Diabetes, Endocrinology and Metabolism
Vanderbilt University Medical Center

Isabelle Ragueneau-Majlessi, MD, MS Matthew J. Sewell, MD, PharmD xiii
Clinical Professor WISE Dermatology
Department of Pharmaceutics Houston, Texas
University of Washington
Seattle, Washington Keith A. Sharkey, PhD, CAGF, FACHS
Professor of Physiology and Pharmacology
Christopher J. Rapuano, MD Cumming School of Medicine
Chief, Cornea Service, Wills Eye Hospital University of Calgary
Contributors
Professor Calgary, Canada
Sidney Kimmel Medical College at Thomas Jefferson University
Philadelphia, Pennsylvania Eric V. Shusta, PhD
Howard Curler Distinguished Professor and
Wayne Ray, PhD R. Byron Bird Department Chair
Professor, Department of Health Policy Department of Chemical and Biological Engineering
Vanderbilt University Medical Center Department of Neurological Surgery
Nashville, Tennessee University of Wisconsin
Madison, Wisconsin
Emanuela Riciotti, PhD
Research Assistant Professor of Pharmacology David R. Sibley, PhD
Department of Systems Pharmacology and Translational Therapeutics Senior Investigator, Molecular Neuropharmacology Section
Perelman School of Medicine National Institute of Neurological Disorders and Stroke
University of Pennsylvania National Institutes of Health
Philadelphia, Pennsylvania Bethesda, Maryland
Anna Tate Riegel, PhD Misty D. Smith, PhD

Professor Research Assistant Professor
Departments of Oncology & Pharmacology Department of Pharmacology & Toxicology
Georgetown University School of Medicine College of Pharmacy and School of Dentistry
Washington, DC University of Utah
Salt Lake City, Utah
Erik D. Roberson, MD, PhD
Rebecca Gale Endowed Professor Peter J. Snyder, MD
Department of Neurology Professor of Medicine
University of Alabama at Birmingham Perelman School of Medicine
Birmingham, Alabama University of Pennsylvania
Dan M. Roden, MD
Professor of Medicine, Pharmacology, and Biomedical Informatics Krishna Sriram, PhD
Senior Vice President for Personalized Medicine Assistant Project Scientist
Vanderbilt University Medical Center Department of Pharmacology
Nashville, Tennessee University of California, San Diego
P. David Rogers, PharmD, PhD, FCCP
St. Jude Endowed Chair in Pharmaceutical Sciences C. Michael Stein, MBChB, FRCP(Edin)
Department of Pharmacy and Pharmaceutical Sciences Dan May Professor of Medicine
St. Jude Children’s Research Hospital Division of Clinical Pharmacology
Memphis, Tennessee Vanderbilt University Medical Center
Carla V. Rothlin, PhD
Dorys McConnell Duberg Professor of Immunobiology and Yuichi Sugiyama, PhD
Pharmacology Distinguished Professor
Yale University School of Medicine Graduate School of Pharmaceutical Sciences
New Haven, Connecticut Josai International University
Kioi-cho, Japan
Natalia Ruiz-Negrón, PharmD
Research Assistant Professor Rebecca Petre Sullivan, PhD
University of Utah College of Pharmacy Associate Professor of Physiology and Vice Chair
Salt Lake City, Utah Department of Biomedical Education and Data Science
Department of Cardiovascular Sciences
Edward A. Sausville, MD, PhD Lewis Katz School of Medicine
Professor of Medicine (Retired) Temple University
Greenebaum Comprehensive Cancer Center Philadelphia, Pennsylvania
University of Maryland
Baltimore, Maryland Zeba A. Syed, MD
Assistant Professor
Robert Schooley, MD Wills Eye Hospital
Distinguished Professor of Medicine Philadelphia, Pennsylvania
xiv Palmer Taylor, PhD Anton Wellstein, MD, PhD
Sandra & Monroe Trout Professor of Pharmacology, School of Medicine Professor of Oncology and Pharmacology
Dean Emeritus, Skaggs School of Pharmacy & Pharmaceutical Sciences Georgetown University School of Medicine
University of California, San Diego Washington, DC
Jürgen Wess, PhD
Steve M. Taylor, MD, PhD Chief, Molecular Signaling Section
Associate Professor of Medicine (Infectious Diseases) and Global Health Lab of Bioorganic Chemistry
Contributors
School of Medicine, Duke University National Institute of Diabetes and Digestive and Kidney Diseases
Durham, North Carolina National Institutes of Health
Bethesda, Maryland
Douglas G. Tilley, PhD
Professor Dawn Wetzel, MD, PhD
Department of Cardiovascular Sciences, and Center for Assistant Professor of Pediatrics and Biochemistry
Translational Medicine University of Texas Southwestern Medical Center
Lewis Katz School of Medicine at Temple University Dallas, Texas
Karen S. Wilcox, PhD
Roberto Tinoco, PhD Professor and Chair of Pharmacology & Toxicology
Assistant Professor College of Pharmacy
Department of Molecular Biology and Biochemistry University of Utah
School of Biological Sciences Salt Lake City, Utah
University of California, Irvine
Irvine, California Aislinn Williams, MD, PhD
Assistant Professor of Psychiatry
John Traynor, PhD Iowa Neuroscience Institute
Edward F. Domino Research Professor University of Iowa
Professor and Associate Chair for Research, Department of Iowa City, Iowa
Pharmacology, Medical School
Professor of Medicinal Chemistry, College of Pharmacy Talene A. Yacoubian, MD, PhD
Department of Pharmacology Professor
University of Michigan Department of Neurology
Ann Arbor, Michigan University of Alabama at Birmingham
Birmingham, Alabama
Shirley M. Tsunoda, PharmD
Professor of Clinical Pharmacy Jingjing Yu, MD, PhD
Skaggs School of Pharmacy & Pharmaceutical Sciences Clinical Associate Professor and Associate Director of UW Drug
University of California, San Diego Interaction Solutions
La Jolla, California Department of Pharmaceutics
University of Washington
Suzanne M. Underhill, PhD Seattle, Washington
Research Fellow
National Institute of Mental Health Jason X.-J. Yuan, MD, PhD
Bethesda, Maryland Professor of Medicine and Director of Physiology
Sara L. Van Driest, MD, PhD La Jolla, California
Associate Professor of Pediatrics, Division of General Pediatric
Associate Professor of Medicine, Division of Clinical Pharmacology Alexander C. Zambon, PhD
Vanderbilt University School of Medicine Assistant Professor of Biopharmaceutical Sciences
Nashville, Tennessee Keck Graduate Institute
Claremont, California
Wendy Vitek, MD
Associate Professor and Medicine Bruce L. Zuraw, MD
University of Rochester Medical Center Professor of Medicine
Rochester, New York University of California, San Diego
Jeffrey I. Weitz, MD, FRCPC, FRSC, FCAHS
Professor of Medicine and Biochemistry and Biomedical Sciences
Canada Research Chair (Tier I) in Thrombosis
Heart and Stroke Foundation J.F. Mustard Chair in
Cardiovascular Research
McMaster University
Hamilton, Canada

Preface
This is the 14th edition of book that began as a collaboration between or that are known only by a trade name. The full text is available online at
two friends and professors at Yale, Louis Goodman and Alfred Gilman. many medical, pharmacy, and nursing schools by institutional subscription
Over the years, “G&G” has been acclaimed as the “blue bible” of phar- to AccessMedicine.com and AccessPharmacy.com, where we publish regular
macology. Surely much of that acclaim reflects the book’s purpose, delin- updates. Feel free to contact the editors by email if you have comments on
eated by the original authors and steadily adhered to over 81 years: to the book or the websites.
correlate pharmacology with related medical sciences, to reinterpret the Editing this book brings to mind a number of larger issues, both
actions and uses of drugs in light of advances in medicine and the basic positive and negative, relating to health care; among them: the
biomedical sciences, to emphasize the application of pharmacodynamics remarkable explosion of molecular genetic techniques, the prolif-
to therapeutics, and to create a book that would be useful to students of eration of therapeutic agents affecting the immune system, and the
pharmacology and to healthcare practitioners. power of computer-aided drug design; antibiotic resistance promoted
Following these principles is demanding: the sheer volume and unre- by the continuing misuse and overuse of antibiotics in healthcare and
mitting growth of knowledge in the basic biomedical sciences and their animal husbandry; the adverse environmental effects of human activ-
clinical applications continue to amaze, challenging editors and contrib- ity to life on Earth; the effects of global warming and the sheer size of
utors who are trying to produce a one-volume work, and surely challeng- the human population on global health and nutrition; the ease with
ing students. To create a book that reflects our times, we have updated all which infectious diseases can spread around the world; the fragility of
chapters and have added five new chapters: drug response and the gas- truth and fact, and the difficulty of promoting health based on science
trointestinal biome, pharmacovigilance, the blood-brain barrier (it is not and data in the face of determined conspiracy theories and political
simply a lipid sheath), cannabinoids, and immunotherapies for cancer, ideology. A better world is possible.
plus a novel appendix on drug-drug interactions. Advances in immu- A number of people have contributed to the preparation of this edition
nomodulation are presented in most sections. In addition, we have con- of Goodman & Gilman. Many thanks to: my co-editor, Bjorn Knollmann,
tinued to reach out to younger contributors who are on the forefront of and to the clinical pharmacology fellows at Vanderbilt whom he recruited
pharmacological investigation and clinical practice. As a result, we have, to read the first drafts of chapters as they honed their editorial skills; our
in this edition, 56 new contributors, drawn from diverse backgrounds, attentive publisher at McGraw Hill, Michael Weitz, and his colleagues
who will ensure the book’s vigor into the future. Christina Thomas and Melinda Avelar; consulting pharmacist Nelda
A multi-authored work such as Goodman & Gilman grows by accre- Murri; Nitesh Sharma at KnowledgeWorks Global Ltd, who tirelessly
tion, deletion, addition, replacement, and repair. The current text reflects oversaw the transformation of Word documents into a printed book;
over eight decades of such activity, with wisdom, memorable pearls, new Jason McAlexander of MPS North America, whose rapid-response art-
material, and flashes of wit, hopefully edited to meet the present and to be work brightens the pages; and the eagle-eyed Becky Hainz-Baxter, who
forward looking. End-of-chapter notes acknowledge retired contributors saw what the editors had missed.
to the 13th edition, but I am happy to acknowledge that several genera- My special thanks to Lynne Larson, a novelist, artist, and grants
tions of editors and contributors have helped to bring this 14th edition to management specialist who managed this enterprise and kept the
its present form. As in the 13th edition, we have used a larger page size, no editors organized. Lynne managed the production of the 11th edition
extract type, and more mechanistic figures as we attempt to explain the of Goodman & Gilman when I first became the editor, when everything
pharmacodynamics of new agents. Some readers have complained that the was done with hard copy and Word files submitted by mail, when galley
book is getting too complex. We believe that a thorough understanding of proofs were actual long sheets of paper on which corrections were hand-
a drug’s actions and interactions at multiple physiological sites and with written and then transcribed to new Word files. I was delighted when
other drugs is essential to modern therapeutics. However, we also prom- Lynne agreed to manage this all-electronic project. We would not have
inently summarize the mechanisms of action, ADME, and clinical use of this 14th edition without her.
individual agents and drug classes. Not wanting to favor one manufactur-
er’s product over that of another, we continue generally to avoid using trade Laurence L. Brunton
names except as needed to distinguish multiple formulations of the same San Diego, CA
agent that have distinct pharmacokinetic or pharmacodynamic properties 14 July 2022

Acknowledgments
Melinda Avelar Becky Hainz-Baxter

Executive Assistant Editorial Specialist
McGraw Hill
Lynne Larson
Marijo Bilusic, MD, PhD Managing Editor
Sylvester Comprehensive Cancer Center
University of Miami Ali Manouchehri, MD
Clinical Pharmacology Fellow
Katherine Black, MD Vanderbilt University
Clinical Pharmacology Fellow Nashville, Tennessee
Pediatric Gastroenterology, Hepatology and Nutrition
Vanderbilt University Jason M. McAlexander
Nashville, Tennessee Biomedical Media Manager
MPS North America LLC
John Brannon, PhD
Clinical Pharmacology Fellow Nelda Murri, PharmD, MBA
Hadjifrangiskou Lab Consulting Pharmacist
Vanderbilt University Bin Ni, PhD
Nashville, Tennessee Clinical Pharmacology Fellow
John Cidlowski, PhD Vanderbilt University
Senior Investigator, NIEHS Nashville, Tennessee
Benjamin Coleman, PhD Jin-Woo Park, MD, PhD

Grueter Lab Graduate, 2022 Clinical Instructor in Neurology
Vanderbilt University Adjunct Instructor in Clinical Pharmacology
Nashville, Tennessee Korea University Medical Center
Seoul, Korea
Gwendolyn Davis, PhD
Clinical Pharmacology Fellow Brittany Spitznagel, PharmD, PhD
Madhur Lab Research Instructor
Vanderbilt University Weaver Lab
Nashville, Tennessee Vanderbilt University
Christian Egly, PharmD
Clinical Pharmacology Fellow Janaki Sharma, MD
Knollmann Lab Assistant Professor of Medicine
Vanderbilt University University of Miami
Nashville, Tennessee Nitesh Sharma
Erica Marie Garner, MD, MSCI Senior Project Manager
Instructor in Medicine KnowledgeWorks Global Ltd.
Vanderbilt University Christina Thomas
Nashville, Tennessee Senior Project Development Editor
Breanne Gibson, PhD McGraw Hill
Research Fellow
Schoenecker Lab
xviii Francisco Villarreal, MD, PhD Amr Tarek Wahba, MD
Professor of Medicine Instructor of Clinical Medicine
UC San Diego School of Medicine Division of Clinical Pharmacology
La Jolla, California Department of Medicine
Nataraja Sarma Vaitnadin, MBBS, PhD, MPH Nashville, Tennessee
Research Fellow
Acknowledgments
Department of Medicine Michael Weitz

Vanderbilt University Sr. Associate Global Publisher
Nashville, Tennessee Medical, Pharmacy & Allied Health Textbooks
McGraw Hill

Section I
General Principles
Chapter 1. Drug Discovery: From Medicinal Plants to
Computer-Aided Drug Design / 3
Chapter 2. Pharmacokinetics: The Dynamics of Drug Absorption,
Distribution, Metabolism, and Elimination / 23
Chapter 3. Pharmacodynamics: Molecular Mechanisms of Drug Action / 43
Chapter 4. Membrane Transporters and Drug Response / 79
Chapter 5. Drug Metabolism / 101
Chapter 6. The Gastrointestinal Microbiome and Drug Response / 119
Chapter 7. Pharmacogenetics and Pharmacogenomics / 131
Chapter 8. Postmarketing Drug Safety / 145
Chapter 9. Principles of Clinical Toxicology / 155
Brunton_Ch01_p0001-p0022.indd 1 29/07/22 2:46 PM

Chapter
1
FROM MEDICINAL PLANTS TO
COMPUTER-AIDED DRUG DESIGN
■■ Early Experiences With Plants
Drug Discovery: From Medicinal Plants to
Computer-Aided Drug Design
Michael K. Gilson and Laurence L. Brunton
DESIGNING LARGE MOLECULES AS DRUGS:

THE RISE OF BIOPHARMACEUTICALS
■■ Drug Discovery or Drug Invention? THE INVESTIGATIONAL NEW DRUG APPLICATION

■■ Target Identification
■■ Target Validation CLINICAL TRIALS
■■ Target Druggability ■■ Role of the FDA
■■ Beyond Single-Protein Drug Targets ■■ The Conduct of Clinical Trials
■■ Protein-Drug Binding: Affinity and Allostery ■■ Determining “Safe” and “Effective”
EXPERIMENTAL APPROACHES TO PERSONALIZED (INDIVIDUALIZED, PRECISION) MEDICINE

DRUG DISCOVERY
PUBLIC POLICY CONSIDERATIONS
■■ Medicinal Chemistry
■■ High Throughput Screening ■■ The Pharmaceutical Industry Operates in a Capitalist Economy
■■ Fragment-Based Drug Discovery ■■ Who Pays?
■■ Emerging Experimental Technologies ■■ Intellectual Property and Patents
■■ Bayh-Dole Act
COMPUTER-AIDED DRUG DISCOVERY ■■ Biosimilars
■■ Using Chemical Similarity to Discover Targeted Ligands ■■ Drug Promotion
■■ Structure-Based Drug Design ■■ Concerns About Global Injustice
■■ Artificial Intelligence in Drug Discovery ■■ Product Liability
■■ “Me Too” Versus True Innovation: The Pace of New Drug Development
The first edition of Goodman & Gilman, published in 1941, helped to

organize the field of pharmacology, giving it intellectual validity and an From Medicinal Plants to Computer-Aided
academic identity. That edition began: “The subject of pharmacology Drug Design
is a broad one and embraces the knowledge of the source, physical and
chemical properties, compounding, physiological actions, absorption, Early Experiences With Plants
fate, and excretion, and therapeutic uses of drugs. A drug may be broadly
The human fascination—and sometimes infatuation—with chemicals
defined as any chemical agent that affects living protoplasm, and few sub-
that alter biological function is ancient and begins with our long expe-
stances would escape inclusion by this definition.” In practice, of course,
rience with and dependence on plants. Because most plants are root-
a chemical or biological agent is considered a legal drug only if it has been
bound, many produce defensive compounds that animals learn to avoid
approved as such by a national regulatory agency, such as the U.S. Food
and humans to exploit or abuse. Thus, the prior of an Arabian convent
and Drug Administration (FDA) or the European Medicines Agency;
came to appreciate coffee (caffeine) after noting the behavior of goats that
these approved compounds are the focus of this book.
gamboled and frisked through the night after eating the berries of the
This first nine chapters of this book, General Principles, provide
coffee plant; women sought to enhance their beauty by using an extract
the underpinnings for these definitions of pharmacology and drugs by
of the deadly nightshade plant, Atropa belladonna (“beautiful lady”),
exploring the physiological, biochemical, and molecular mechanisms of
enriched in atropine, to produce pupillary dilation; the Chinese herb ma
drug action. This section covers drug invention, development, and reg-
huang (ephedrine) was used as a stimulant; indigenous people of South
ulation, as well as how drugs act in biological systems, i.e., pharmacody-
American used curare to paralyze and kill animals hunted for food; and
namics, pharmacokinetics (including drug transport and metabolism), the
poppy juice (opium), containing morphine (from the Greek Morpheus, the
influence of the gastrointestinal microbiome, and pharmacogenetics, with
god of dreams), has long been used for pain relief and control of diarrhea.
brief forays into pharmacovigilance and drug toxicity and poisoning. Sub-
Morphine, of course, has well-known addicting properties, as do other
sequent sections deal with the use of specific classes of drugs as therapeu-
psychoactive natural products, such as nicotine, cocaine, and ethanol.
tic agents in human subjects. The present chapter is an introduction to
Note that these drugs did not derive from a search for a druggable target
pharmaceuticals, their development, and the activities of the pharmaceu-
or any knowledge of a target. Rather, drug discovery in the past often
tical industry and government surrounding the discovery, production,
resulted from serendipitous observations of the effects of plant extracts or
and use of therapeutic agents. The processes of discovery and invention
individual chemicals on animals or humans. Drugs were selected based
of drugs have changed substantially with the general progress of bio-
on effect, with no understanding of mechanism as we use the term today.
medical sciences, the advent and improvement of computer-aided drug
In the 20th century, the hunt for natural products broadened, driven in
design, and technical advances in biochemistry and molecular biology.
part by the discovery of antibiotics, such as penicillin and the cephalospo-
Some of these new capabilities are reviewed below.
rins, which fungi and microbes make to compete with each other.
4
Abbreviations then use this information to steer the program of chemical synthesis and
testing toward increasingly potent compounds.
In the 1980s, it became practical to determine high-resolution
ADME: absorption, distribution, metabolism, and excretion three-dimensional structures of complex organic molecules and even
BLA: Biologics License Application larger molecules such as proteins, using and refining the techniques of
CADD: computer-aided drug discovery X-ray crystallography pioneered by Hodgkin, Kendrew, and Perutz in
CHAPTER 1 DRUG DISCOVERY: FROM MEDICINAL PLANTS TO COMPUTER-AIDED DRUG DESIGN
DEL: DNA-encoded compound library the mid-20th century. It was already known that many drugs worked
DHHS: U.S. Department of Health and Human Services by binding tightly to a disease-related protein and thereby modulating
DMPK: drug metabolism and pharmacokinetics (e.g., inhibiting or activating) its biological function, but the atomic
FBDD: fragment-based drug discovery details of these interactions had remained mysterious. As a consequence,
the only way to advance a drug discovery project had been by synthesizing
FDA: U.S. Food and Drug Administration
and testing one compound after another. Now, with the protein’s three-
GPU: graphics processing unit
dimensional structure in hand, one could finally hope to design a com-
HCV: hepatitis C virus
pound that would bind with high affinity by fitting snugly into a pocket
HDL: high-density lipoprotein
in the protein, such as an enzyme’s active site. Thus, protein crystallog-
HMG-CoA: 3-hydroxy-3-methylglutaryl coenzyme A
raphy enabled structure-based drug design (SBDD), where the three-
HTS: high-throughput screening
dimensional structure of the drug target is used to guide creation of
IND: Investigational New Drug tight-binding compounds, often called ligands.
LDL: low-density lipoprotein Around the same time, computer technology began to advance
mRNA: messenger RNA rapidly. This accelerated the data processing needed to go from X-ray
NDA: New Drug Application diffraction patterns to protein structures (i.e., three-dimensional atomic
NIH: National Institutes of Health coordinates) and enabled interactive visualization of complex protein
NMEs: new molecular entities structures comprising thousands of atoms. It also opened new vistas in
PDUFA: Prescription Drug User Fee Act computer-aided drug discovery (CADD), including the use of molecular
SBDD: structure-based drug design simulations to model the physical interactions of compounds and pro-
siRNA: small interfering RNA teins, and the development of tools to encode, archive, share, and analyze
chemical and pharmacological data. In parallel, automation and minia-
turization have dramatically increased experimental throughput, notably
through robotic high-throughput screening (HTS), in which hundreds
Drug Discovery or Drug Invention? of thousands of compounds can be tested rapidly and at relatively low
The conventional phrase drug discovery makes sense for therapeutic com- cost in cellular or molecular activity assays. Today, excitement about the
pounds obtained from plants and other organisms. Today, however, only power of artificial intelligence motivates wide-ranging efforts to apply
a fraction of the new drugs introduced each year are discovered in nature. these technologies to drug discovery.
Instead, most drugs are not discovered, but are totally new compounds, The following section goes into more detail regarding the process of
painstakingly optimized against many criteria through an interplay of drug discovery, focusing on so-called small-molecule drugs, organic com-
design and experimentation. In that sense, today’s new drugs are more pounds with molecular weights typically less than 500 Da, which have
invented than discovered. traditionally been the most common type of drug. Subsequent sections
The current paradigm for drug development grew out of synthetic introduce biological drugs, such as antibodies and other engineered
organic chemistry, which arose as the dye industry in the late 19th biomolecules.
century and has continued to flourish. Dyes are colored compounds
with selective affinity across various biological tissues. Study of these Target Identification
interactions stimulated Paul Ehrlich to postulate the existence of Today, most small-molecule drug discovery projects grow out of basic
chemical receptors in tissues that interacted with and “fixed” the dyes. research that implicates a specific macromolecule, usually a protein, as a
Similarly, Ehrlich thought that unique receptors on microorganisms key player in a disease and, further, suggests that a small molecule which
or parasites might react specifically with certain dyes and that such binds this macromolecule could be used to treat the disease. The macro-
selectivity could spare normal tissue. Ehrlich’s work culminated in the molecule thus becomes a candidate drug target. Many small-molecule
invention of arsphenamine in 1907, which was patented as “salvarsan,” drugs are inhibitors (antagonists), which work by reducing the activity of
suggestive of the hope that the chemical would be the salvation of their macromolecular target. Examples include the statins, which reduce
humankind. This and other organic arsenicals were used to treat syph- cholesterol synthesis by binding and inhibiting the enzyme 3-hydroxy-3-
ilis until the discovery of penicillin. Gerhard Domagk demonstrated methylglutaryl (HMG) coenzyme A (CoA) reductase, and β-lactam antibi-
that another dye, prontosil (the first clinically useful sulfonamide), otics, which kill bacteria by inhibiting enzymes involved in the synthesis of
was dramatically effective in treating streptococcal infections, thereby bacterial cell walls. However, some small molecules are activators (agonists)
launching the era of antimicrobial chemotherapy. The collaboration of rather than inhibitors. Activators frequently target proteins whose normal
pharmacology with chemistry on the one hand and clinical medicine role involves cell signaling, such as hormone receptors. For example, the
on the other has been a major contributor to the effective treatment of asthma medication albuterol dilates bronchi by binding and activating β
disease, especially since the middle of the 20th century. adrenergic receptors on bronchial smooth muscle, thereby mimicking the
Early on, new compounds could be tested for their activities only in effect of adrenaline (epinephrine; see Chapter 10).
whole organisms. This is how the nonsteroidal anti-inflammatory drug Candidate drug targets have been identified in many ways
indomethacin was discovered, for example (Brune and Hinz, 2004). In (Hughes et al., 2011). For example, the enzymes targeted by the β-lactam
the past 70 years, researchers have begun to understand in considerable antibiotics were unknown in advance and were discovered precisely
detail the cellular and molecular mechanisms of disease. As a result of this because they are bound by these naturally occurring antibiotics. In con-
basic biomedical research, it is possible to do initial testing of compounds trast, the target of the statins, HMG-CoA reductase, was identified by
in vitro (“in glass”), using cellular and molecular assays. For example, elucidation of the pathways of cholesterol synthesis (Tobert, 2003), and
one could look for the cellular responses due to inhibition of a protein this information was used to help discover the first statins. Similarly, as
involved in a disease process. In this scenario, by testing enough appro- researchers have determined the regulatory functions of human protein
priately chosen compounds, one could develop at least a partial under- kinases—enzymes that change the activities of other proteins by cova-
standing of which types of compounds are most likely to be active and lently attaching phosphate groups to their hydroxyl-containing side

chains—specific kinases have been targeted for small-molecule drug target validation aims to “de-risk” a project by lowering the probability 5
discovery (Cohen et al., 2021). Many kinase inhibitors are anticancer that a compound carefully developed to hit the targeted protein will fail
agents that work by inhibiting protein kinases that accelerate cell prolifer- in clinical trials, whether because hitting the target does not influence
ation. Some of these targeted kinases carry abnormal, cancer-associated the disease as expected or because the compound generates unanticipated
mutations that make them hyperactive, so inhibiting them returns their toxicity, termed on-target or mechanism-based toxicity.
SECTION I
regulatory activities toward normal. The pioneering example of this sce- There are no absolute criteria for target validation, nor is there a single
nario is the drug imatinib, which inhibits a cancer-associated mutant method. One approach is to use a chemical probe, a small molecule that
protein kinase, the Bcr-Abl tyrosine kinase, and is used to treat chronic binds the target, and study its biological effects (Quinlan and Brennan,
myelogenous leukemia (Buchdunger et al., 2002). 2021). This approach requires that such a probe be available, and the
In recent years, technological advances enabling genome-wide experi- fields of chemical genetics (Stockwell, 2000) and chemogenomics (Bredel
mentation (omics) have opened new approaches to identifying candidate and Jacoby, 2004) aim to create selective chemical probes for as many
targets (Lindsay, 2003; Paananen and Fortino, 2020). Fast, inexpensive proteins in the human genome as possible. Alternatively, one may use
GENERAL PRINCIPLES
genome sequencing facilitates genome-wide association studies, in which gene silencing via small interfering RNA (siRNA) to block production
variations in the susceptibility to a disease across many people are cor- of the target protein, thereby mimicking the effect of an inhibitor of the
related with variations in specific genes, leading to suggestions for gene protein’s activity. Additional insight into the biological role of a candidate
products (i.e., proteins), that may be suitable drug targets. The growing drug target may sometimes be obtained by studying genetically modified
availability of patient genomic data in the context of patients’ electronic mice, including knockout mice, in which the gene coding for the target
medical records will likely open new opportunities for data mining in has been disabled entirely, and transgenic mice, in which expression of
support of target discovery in the coming years. It has also become routine the target’s gene is placed under the control of a promoter that can be
to measure the quantities of messenger RNA (mRNA) transcribed from turned on by feeding the animals a specific compound, such as tetracycline
thousands of genes simultaneously (the transcriptome) and to quantify (Lindsay, 2003).
thousands of translated proteins (proteomics). By comparing such data
between, for example, cancer cells and normal cells, one can identify pro- Target Druggability
teins transcribed or present at elevated or depressed levels in the disease
It is important to know whether the candidate target is drug-
state. Mining data about these proteins from sources such as biomedi-
gable, that is, whether it can, in principle, bind a small molecule with suf-
cal databases, scientific articles, and patents, and integrating it with the
ficient affinity. If the protein has been the target of a prior drug discovery
omics data, may suggest certain proteins as candidate drug targets.
effort, there may be informative small-molecule binding data in a public
A totally different approach starts with the use of high-throughput
database, such as BindingDB (Gilson et al., 2016), PubChem (Kim et al.,
instrumentation and robotics to test a large collection of small molecules
2021), or ChEMBL (Gaulton et al., 2012), or in an article or patent not
(a chemical library) for biological activity in a phenotypic screen (Swinney
yet curated by one of these databases. One may also check the Protein
and Lee, 2020), which might use automated microscopy and image anal-
Data Bank (Berman et al., 2000; Berman and Gierasch, 2021) for a crystal
ysis to determine which compounds produce desired biological effects,
structure of the target, which may assist in locating a suitable binding
such as the activation of a desired gene in cultured human cells or the
pocket for the small molecule to be developed as a drug. This is frequently
death of a parasitic microorganism in culture. Various methods may then
true for metabolic enzymes and receptors that have evolved to bind small
be used for target deconvolution (i.e., to determine how the active small
substrate and transmitter molecules. Many proteins belong to families,
molecules work). For example, candidate targets of compounds found to
such as the protein kinases, whose members have similar properties
kill the malarial parasite Plasmodium falciparum were identified by cul-
(e.g., an ATP binding pocket), so that if one member of a family is drug-
tivating these organisms in gradually increasing concentrations of the
gable, then the others probably are also. In contrast, receptors for proteins
compound to select for resistant protozoa and then using omics methods
often have large, relatively flat binding surfaces, rather than small binding
to determine which genes had changed. The proteins encoded by these
pockets suitable for a small-molecule drug, and are thus less likely to
genes may then become candidate drug targets (Flannery et al., 2013).
be druggable and influenced by small molecules. Efforts are under
way to systematically search for all druggable targets encoded by the
Target Validation human genome (Nguyen et al., 2017; Finan et al., 2017; Hopkins and
After a candidate drug target has been identified, additional research is Groom, 2002) and to gain traction against targets hitherto considered
usually warranted to validate it by seeking stronger evidence that a small undruggable (Dang et al., 2017).
molecule that binds and modulates it will actually treat the disease (Jones, The ultimate validation of a candidate target is the successful devel-
2016; Lansdowne, 2018; see Box 1–1). For example, the fact that a protein opment of a novel drug that works by binding to it. Such a novel drug is
is more abundant in cancer cells than normal cells by no means proves termed first-in-class. A first-in-class drug is a true innovation and may
that it is a suitable drug target. Instead, this might be a correlate rather represent a medical breakthrough, so one might expect first-in-class to
than a cause, so further research is needed to assess its role. Accordingly, be the goal of every drug discovery project. In fact, however, pharma-
ceutical companies often engage in less innovative, more predictable
projects by developing me-too drugs against old targets that are already
BOX 1–1 ■ Target Validation: The Lesson of Leptin fully validated by a first-in-class drug. Such projects aim to improve on
the first-in-class drug through, for example, greater potency, reduced
Biological systems frequently contain redundant elements or can side effects, or more convenient dosing (e.g., oral instead of intravenous),
alter expression of drug-regulated elements to compensate for the and ideally to produce a new drug considered best-in-class. For example,
effect of the drug. In general, the more important the function, the Merck’s lovastatin broke ground as the first statin, the first in a class of
greater the complexity of the system. For example, many mechanisms drugs that lower cholesterol by inhibiting the enzyme HMG-CoA reduc-
control feeding and appetite, and drugs to control obesity have been tase (see Chapter 37); but other statins, such as atorvastatin, have also
notoriously difficult to find. The discovery of the hormone leptin, achieved enormous commercial success.
which suppresses appetite, was based on mutations in mice that cause
loss of either leptin or its receptor; either kind of mutation results in
enormous obesity in both mice and people. Leptin thus appeared to be Beyond Single-Protein Drug Targets
a marvelous opportunity to treat obesity. However, on investigation, A number of drugs, whether by accident or by design, hit multiple pro-
it was discovered that obese individuals have high circulating tein targets, a phenomenon termed polypharmacology (Peters, 2013).
concentrations of leptin and appear insensitive to its action. This phenomenon is particularly common when the target is a mem-
ber of a family of proteins with similar binding sites. For example, the

6 full physiological effect of an adrenergic antagonist is determined by • The hydrophobic effect, in which nonpolar or “greasy” parts of the
its actions across the family of adrenergic receptor types and subtypes. drug and protein associate with each other to reduce their energeti-
Similarly, many protein kinase inhibitors inhibit multiple kinases, each cally unfavorable exposure to water, much as oil droplets coalesce in
to a different degree. There are instances where hitting multiple targets salad dressing
is fruitful, such as inhibiting sequential reactions in a series. Modulating • Dispersion forces—the attractive part of van der Waals interactions—
multiple proteins in a single biochemical pathway or signaling network short-ranged attractive interactions between the instantaneous elec-
overcomes the evolved redundancy of a robust biological system and trical dipoles that result from the constant fluctuations of negatively
hence leads to greater efficacy than modulating only one protein. A single charged atomic electron clouds around positively charged atomic
compound may, alternatively, hit two entirely different targets in different nuclei
pathways, although this is more challenging to achieve without going to
larger compounds. The analysis of complex molecular systems in relation These attractive forces need to overcome the entropic tendency of
to drug action is termed systems pharmacology. the drug and protein to wander apart, due to thermal energy. There are
Polypharmacology is not always beneficial, and indeed, it can lead to also, inevitably, forces that oppose binding and that must be overcome by
toxicity. Some of the unintended effects of a drug will be termed side the attractive ones. For example, there is an energy penalty for stripping
effects or even major adverse drug responses. For example, a number of water from polar chemical groups of the ligand and protein as they come
initially promising compounds have proven to bind and inhibit hERG, together to bind. Thus, the overall affinity of a drug-protein interaction
the K+ channel in the heart that mediates repolarization (the IKr current; reflects a delicate and hard-to-predict balance of attractive and repulsive
see Chapter 34); inhibition of hERG can lead to potentially fatal arrhyth- interactions.
mias. The hERG channel has, therefore, become a notorious anti- Small-molecule drugs do not bind to the relatively smooth, exterior
target that must be scrupulously avoided by drug discovery projects surfaces of their protein targets, but instead are enfolded by binding pock-
(Garrido et al., 2020). ets in the protein (see Figure 1–4). This structural arrangement makes it
Some small-molecule drugs do not bind to proteins at all. For exam- possible to form the extensive, short-ranged, physical interactions that
ple, platinum anticancer drugs, such as carboplatin, kill cancer cells by are needed to hold the two molecules together tightly. Druggable binding
binding covalently to DNA; the aminoglycoside antibiotics block bacte- pockets (i.e., ones that enable small-molecule binding) usually are avail-
rial protein synthesis by binding to RNA within the bacterial ribosome; able in enzymes whose substrates are small molecules and in receptors
and antiviral nucleoside analogues are incorporated into viral DNA in that bind small-molecule hormones and transmitters. However, many
place of normal nucleosides and then block DNA replication. The drug proteins lack a concave pocket and therefore are difficult or impossible
sugammadex has both an unusual purpose and an unusual mechanism. to drug with a small molecule. In such cases, one may instead consider
Surgical patients often receive not only general anesthesia but also the developing a protein therapeutic, such as an engineered antibody that
nondepolarizing neuromuscular blocking agent rocuronium, which targets the protein of interest. Because proteins are large, they can form
prevents involuntary movements of skeletal muscle during surgical extensive, short-ranged, physical interactions even with the relatively flat
procedures (see Chapter 13). Sugammadex, a larger, cup-shaped mole- exterior surface of a targeted protein, and thus can achieve adequate bind-
cule, binds and sequesters rocuronium. Thus, injection of sugammadex ing affinity where a small-molecule drug cannot. These considerations
rapidly reduces the concentration of unbound rocuronium in the blood also help explain why it is difficult to develop a small-molecule drug that
and promptly reverses paralysis when a procedure is complete. will block a protein-protein interaction: protein-protein binding usually
involves a large number of interactions on a relatively flat binding inter-
face between the two proteins, and a small molecule cannot get sufficient
Protein-Drug Binding: Affinity and Allostery purchase on such a flat surface.
A successful drug with a protein target must bind to its target with high Note that a drug must not only bind to its target but also have the
affinity so that even a small dose of the drug will yield a blood concen- desired effect upon it. If the goal is to inhibit an enzyme, then a drug
tration high enough to bind a large fraction of the targeted protein. If the that binds in the active site should easily accomplish this by simply
affinity were low, then a high concentration of drug would be needed for blocking association of the enzyme with molecules of substrate. In
a substantial fraction of the target sites to be occupied, and a large dose contrast, when a cell-surface receptor is the target, a small molecule
of drug would need to be administered, leading to inconvenience and might interact at the agonist binding site but without inducing an acti-
an increased risk of side effects. The affinity of a small molecule for a vating conformational change and thus might function as an antag-
protein is generally given as the dissociation constant, the concentration onist or inverse agonist (see Chapter 3). A drug may also inhibit the
of free drug molecules in solution at which 50% of the targeted protein function of a protein by binding in a pocket outside the active site, and
has bound drug; the lower this concentration, the higher the affinity (see thereby modifying the three-dimensional conformation of the targeted
Figure 3–3). Drug design projects typically aim for a dissociation con- protein; this is an allosteric effect. Such a drug must not only bind in
stant on the order of 10–9 mol/L (1 nM); such a “nanomolar drug” is typi- a suitable pocket but also induce the desired conformational change.
cally dosed in milligrams to grams per day. A successful drug should also Efavirenz and nevirapine, used in treating HIV-AIDS, are nonnucle-
exhibit a high degree of specificity for its target protein, meaning that the oside reverse transcriptase inhibitors that act allosterically to inhibit
drug does not interact with other proteins that could lead to undesired viral transcription of viral RNA to DNA (see Figure 65–5). Similarly,
side effects and toxicity. In some cases, the effectiveness of a drug may a number of ligands interact with allosteric sites on GABAA receptors
be influenced by not just the affinity but also the kinetic rate constants (see Figure 16–11) and other Cys-loop receptors to modulate receptor/
for drug-protein binding and dissociation, which determine the drug’s channel function. Allostery can also offer a sophisticated strategy to
residence time at its receptor (Copeland, 2016). target a single enzyme from among a family of similar enzymes. Thus,
Most drugs bind their targeted proteins via attractive, intermolecular inter- in designing a drug, one might take advantage of the fact that, even
actions that do not involve a covalent chemical bond. These noncovalent within a family of related proteins with similar active sites, the members
interactions typically include: will likely have other regions of their structure that are more variable
and possibly unique. Designing a small ligand that binds to such a site
• Hydrogen bonding, in which an electronegative atom with a bound might produce an agent that is a quite selective allosteric modifier of
hydrogen atom, such as a hydroxyl group, partly shares its hydrogen enzyme function. This approach is being used to target selected protein
with an electronegative atom on the other molecule phosphatases (Mullard, 2018).
• Attractive electrostatic interactions between atoms of opposite charge, A few small-molecule drugs react chemically with their protein targets
such as between a negatively charged carboxylic acid belonging to the to form irreversible, covalent bonds, rather than relying entirely on the
drug and a positively charged arginine side chain of the protein noncovalent attractions discussed above. Such covalent drugs bond to a

specific chemical group of the protein target, often a relatively reactive Medicinal Chemistry 7
amino acid side chain within an enzyme’s catalytic site. In principle,
Synthetic organic chemistry remains at the heart of small molecule drug
covalent drugs should require smaller, less frequent dosing, because a
discovery, where it is specialized and known as medicinal chemistry.
covalently bound drug will not dissociate from the protein as the con-
Medicinal chemists typically are part of a project team that includes,
centration of free drug dwindles over time following a dose (but note
among others, biologists, assay specialists, and computational chemists;
that some boron-containing compounds form reversible covalent bonds
SECTION I
their role is to reduce chemical concepts to practice by synthesizing and
[Diaz and Yudin, 2017]). Drug developers have tended to avoid cova-
purifying compounds that may ultimately lead to a new drug. In addition
lent drugs because they necessarily possess chemically reactive groups
to providing the expertise needed to synthesize compounds of interest,
that risk reacting not only with the desired target but also with other
they also help guide the design and selection of the compounds to be
proteins and biomolecules, with the potential for causing undesired
made. A key consideration is the complexity of a compound’s synthesis,
biological effects. However, selectivity can be achieved by specific non-
or “synthetic accessibility”, which must be balanced against the level of
covalent interactions between the drug and the protein that pull the
GENERAL PRINCIPLES
interest in the compound. For example, it can be difficult to generate
compound into a location and conformation where it is poised to form
pure stereoisomers of compounds with multiple chiral carbon atoms, and
the desired covalent bond.
certain chemical structures can by synthesized only via demanding, mul-
Covalent binding has been used to successfully target and inhibit
ti-step syntheses. A compound that is too difficult to make or purify will
a member of the RAS GTPase family, KRAS G12C, which had been
not only slow down the research effort but may also lead to a drug that is
viewed as virtually undruggable. As a result of such targeted posi-
too costly to manufacture.
tioning, the cancer drug sotorasib gains both potency and specificity
Medicinal chemists also inform the drug design process by providing
by forming a covalent bond with a cysteine side chain present in an
insights into the properties of various chemical groups that might be
oncogenic mutant form of KRAS but not in normal KRAS (Lanman
incorporated into a drug, such as the attractive or repulsive interactions
et al., 2020).
they may form with the targeted protein, their susceptibility to metabolic
changes following administration, their potential to spontaneously form
undesired covalent bonds with biomolecules, and their influence on the
Experimental Approaches to Drug Discovery compound’s ability to cross the blood-brain barrier (which may be desir-
Given a validated target, the next major milestone in a drug discovery able or undesirable, depending on the goal of the project). This expertise
project is arrival at a clinical candidate, a small molecule that binds the comes into play, for example, when a compound binds the target well but
target with high affinity and specificity, has the desired effect on it, is rapidly metabolized by the liver into an inactive product. In this setting,
and meets a range of other criteria for a safe, efficacious drug (Hefti, the medicinal chemist may try substituting the part of the compound that
2008). Some of these criteria relate to pharmacokinetics: How well will is metabolized with a “bioisostere”, a different chemical group with a sim-
the compound be absorbed if given orally? How well does it distribute ilar shape and ability to interact with the protein but with reduced suscep-
to the targeted organs and tissues? How rapidly and by what mecha- tibility to metabolic modification. More broadly, decades of experience
nisms is it eliminated? Is it metabolized to an active metabolite? These have led to a number of rules of thumb for what makes a compound
properties are often lumped together as absorption, distribution, “drug-like”, such as the “rule of five” (Lipinski, et al., 2001). These may
metabolism, and excretion (ADME) or drug metabolism and pharma- be useful guides during drug discovery projects, but there are also many
cokinetics (DMPK). exceptions to the rules (Zhang et al., 2007).
It is also essential to confirm that the compound does not show evi-
dence of toxicity. Both pharmacokinetics and toxicity can be initially High-Throughput Screening
studied in vitro. For example, there are in vitro methods that examine If nothing is known about the structure of the target protein and what
the ease with which the compound enters cells (see Chapter 4) and the small molecules can bind it, it is common to turn to HTS, in which thou-
likelihood that liver enzymes (see Chapter 5) will chemically modify the sands or millions of compounds are tested using automation and robotics
compound. Compounds also can be evaluated in vitro for evidence of (Wildley et al., 2017). Tiny samples of each compound are drawn from
toxicity and mutagenicity. However, in vitro studies cannot fully model a stored chemical library and deposited into multiwell plates for testing.
the complexities of a living organism; animal studies are still required to Substantial effort often must be invested to devise an assay that works reli-
minimize the chances that a compound will be problematic when first ably in miniature and without user intervention. Most provide an optical
given to human subjects. For example, toxicity is usually assessed by long- readout, such as a change in luminescence, fluorescence, or color, as these
term monitoring of the health of two species of animals, generally one can be efficiently measured with an optical plate reader. The compounds
rodent (usually mouse) and one nonrodent (often rabbit), when dosed screened can range from part of the vast, in-house compound collection
with the compound. A good clinical candidate should also meet some that a major pharmaceutical company has assembled over the years to a
nonbiological criteria. In particular, it must be amenable to large-scale smaller set purchased from a commercial vendor. A screening library is
synthesis and high-grade purification at acceptable cost, and it should be often designed for the particular application. For example, one can pur-
possible to create a formulation (e.g., a tablet or injection) that is suffi- chase libraries tuned for activity against protein kinases, libraries with
ciently water soluble and stable. reactive groups that can form covalent bonds to the protein, and libraries
Sophisticated technologies have been developed to speed the process designed to sample a wide range of compounds through high chemical
of generating a clinical candidate. These mainly focus on the discov- diversity. A compound chosen at random from a screening library has a
ery or design of compounds that will bind the protein target with high very low probability, typically 0.1% or less, of being active against a given
affinity (potent ligands). Less progress has been made toward designing target (Shun et al., 2011), and HTS measurements are subject to experi-
in safety and favorable pharmacokinetics. These properties pose more mental error. Therefore, many of the compounds that appear active on an
complex challenges, because they go far beyond how a small molecule initial screen (hit compounds) are false positives, so careful data analysis
and a protein interact with each other and instead involve the interac- and confirmatory testing are essential.
tions of the small molecule with thousands of different biomolecules in Even the confirmed hits from a high-throughput screen are far from
a living system. The technologies for ligand discovery are both experi- being drugs. Their affinity for the target usually is orders of magnitude
mental and computational, and different methods are applicable in dif- too weak, they may lack the desired specificity, and they do not meet
ferent settings. The following subsections touch on broad approaches DMPK or safety criteria. However, they offer an initial toehold on the
but are not comprehensive. Note, too, that various approaches can challenge of finding a potent drug candidate. The next step is to purchase
be used in combination, so the distinctions made here are ultimately (analogue by catalog) and/or synthesize (medicinal chemistry) similar
somewhat artificial. compounds that ultimately give a picture of how various changes in
8 1 O
Compound ALDH1A1 ALDH2 ALDH3A1
O
N 1 0.02 82 7.7
2 0.06 2.1 16
O
2 Cl 4 O
3 0.58 2.1 69
O
N O 4 0.07 3.5 0.45
N
5 0.07 >100 0.31
O 6 2.0 0.05 18
3 Br 5 O
O
N O
N
6 O
Br
O
N
Figure 1–1 Structure-activity relationship: scaffolds and substituents. Five inhibitors of the aldhyde dehydrogenase family of enzymes have a common chemical
scaffold (black) while having different chemical substituents at two positions (red, green). The table lists the IC50 (μM) of each compound for three members
of the aldehyde dehydrogenase family of enzymes: ALDH1A1, ALDH2, and ALDH3A1; i.e., the concentration of compound needed to provide 50% inhibition
of each enzyme. The lower the IC50, the more potently the compound inhibits the enzyme. Focusing first on compounds 1, 2, and 3, one can see that adding an
increasingly bulky halogen atom (Cl, Br) on the six-membered ring tends to reduce the compound’s potency against ALDH1A1 and ALDH3A1 but to increase
it against ALDH2. Focusing next on compounds 1, 4, and 5, one can see that adding increasingly bulky, nonpolar, aromatic substituents at the nitrogen modestly
reduces the potency against ALDH1A1, initially improves but then destroys potency against ALDH2, and consistently improves potency against ALD3A1. Such
patterns can guide the design of new compounds with desired potency and selectivity. For example, the substituents in compounds 3 and 4 each reduce potency
against ALDH1A1 while increasing potency against ALDH2, so it is not surprising that compound 6, which combines both substituents, has particularly low
potency against ALDH1A1 and high potency against ALDH2. Note, however, that this kind of reasoning can only offer guidelines; its predictions are not always
borne out by experiment. Data drawn from Kimble-Hill et al., 2014.
the chemical structure influence activity against the target (structure- to the protein. This information can be used to stitch together designed
activity relationships, or SAR) and other properties (Figure 1–1). This compounds that place the appropriate fragments at the right places in the
information is used to guide the synthesis of often hundreds of com- protein’s binding pocket (fragment linking) or to optimize and expand one
pounds with gradually improving properties. The most promising early selected fragment (fragment growing). In this way, FBDD avoids the com-
molecules (lead compounds) serve as starting points for further improve- binatorial explosion of possible compounds made from various chemical
ment (lead optimization), ultimately generating, hopefully, a clinical components and allows researchers to focus quickly on compounds made
candidate, potentially accompanied by several backup compounds in case from only a productive subset of chemical components. The drug vemu-
the leading candidate fails. rafenib, which targets an oncogenic mutation of B-Raf kinase and was
developed with a fragment-growing strategy, is usually referenced as the
Fragment-Based Drug Discovery first FBDD success story (Bollag et al., 2012).
Even a large-scale screen can fail to provide useful hits (Keserü and
Makara, 2009). This result becomes understandable when one recognizes Emerging Experimental Technologies
that the number of stable, drug-sized, organic compounds is on the order The difficulty and cost of drug discovery, coupled with the market and
of 1060 (Reymond et al., 2010), so a screen of even 106 compounds scarcely human need for new medications, have driven ongoing innovation in
touches the vastness of chemical space. This vastness results from the com- drug discovery technologies. For example, DNA-encoded compound
binatorial explosion of ways of connecting various chemical substruc- libraries (DELs) dramatically expand the number of compounds that
tures, such as benzene rings, hydroxyl groups, and cycloalkanes. To be can be tested, relative to conventional HTS (Halford, 2017). Unlike a
a good binder, a compound has to get multiple substructures positioned traditional HTS compound library, where each compound is kept in its
so they all form favorable interactions with complementary groups in the own separate container or well, a DEL is a mixture of compounds in a
targeted binding pocket. If it has two chemical components suitable for single container and can include far more compounds—into the billions
binding the target but a third that is inappropriate or in the wrong place and even trillions. Each unique compound in the mixture is covalently
on the compound, it may fail to bind the target. This perspective moti- bound to a corresponding unique short DNA molecule, which serves as
vates another method of discovering binders, fragment-based drug dis- an identification tag. Such libraries can be synthesized and tagged with
covery (FBDD) (Erlanson, 2012; Lamoree and Hubbard, 2017). In FBDD, the methods of combinatorial chemistry, where a mixture of compounds
one conceptually breaks down drug-sized compounds into their sub- is split into multiple portions, each portion is modified with a different
structures (fragments) and tests simple substructures against the target. chemical step and its DNA tags modified accordingly, and the portions
Although such fragment-like molecules can bind only very weakly, such are mixed again. This process is iterated until the synthesis is complete.
studies can, nonetheless, identify a small set of chemical substructures To screen the DEL for active compounds, one may immobilize the target
that are suitable for the target, and one can then buy or synthesize larger of interest on a solid surface, expose the surface to the DEL mixture, and
compounds assembled from these components. When either X-ray crys- then wash the surface to remove all the DEL compounds that have not
tallography (Patel et al., 2014) or nuclear magnetic resonance spectros- bound tightly to the target. The binders are then removed from the target
copy (Shuker et al., 1996) is used to detect or analyze fragment binding, by more aggressive washing, and the active compounds in the wash are
specific information is usually available about where each fragment binds identified by sequencing the DNA tags they carry.

Another emerging technology, sometimes termed clinical trials in a dish instead computes tens or hundreds of quantitative descriptors for each 9
(Alpeeva et al., 2017; Fermini et al., 2018; Strauss and Blinova, 2017), aims compound. Examples include simple descriptors, such as molecular
to predict the effects of a compound in humans more accurately than is pos- weight or number of aromatic rings, and more complex descriptors such
sible with standard cell culture or animal models. This approach involves as electrical dipole and quadrupole moments. If one imagines descriptors
creating specific cell types of interest from human pluripotent stem cells and as Cartesian coordinates in a multidimensional space, one can then quan-
SECTION I
using them to create three-dimensional organoids in culture (Fligor et al., tify the similarity of two molecules in terms of how close they are in this
2018; Liu et al., 2021; Sato and Clevers, 2013) or artificial tissue architectures descriptor space (Wale et al., 2008).
via three-dimensional bioprinting (Ferrer and Simeonov, 2017). These rela- Similarity metrics such as these enable virtual screening, a fast, inex-
tively intricate in vitro constructs promise to better recapitulate the proper- pensive, computational alternative to experimental HTS (Figure 1–3).
ties of the corresponding in vivo tissues and may be used to test compounds In this approach, every compound in a chemical library—a large set of
for activity, DMPK properties, compound metabolism, and toxicity. compounds that are available or synthesizable—is assessed for its simi-
larity to one or more known ligands of the protein target. The most sim-
GENERAL PRINCIPLES
ilar compounds are tested in an experimental assay, and confirmed hits
Computer-Aided Drug Discovery become candidates for further chemical optimization. This approach is
most relevant when the three-dimensional structure of the targeted pro-
The rise of information technology has enabled the research community
tein has not been determined. When the structure is known, powerful
to store and move large quantities of information, to write and maintain
structure-based methods become applicable.
complex software, and to do calculations at unprecedented speed and
scale. These continually improving capabilities are used in a variety of
ways to support and accelerate drug discovery. Thus, chemical informat-
Structure-Based Drug Design
ics enables compact databasing of information on hundreds of millions The detailed three-dimensional structure of a targeted protein opens up a
of compounds and rapid recovery of chemical data for a specific com- range of additional computational methods for designing a small molecule
pound and/or chemically similar compounds (Willett et al., 1998), while that binds the target with high affinity (Figure 1–4). The applicability of
the Internet makes chemical (Gaulton et al., 2012; Gilson et al., 2016; Kim such SBDD methods has grown continually, due to rapid increases in com-
et al., 2021), macromolecular (Benson et al., 1994; Berman et al., 2000; puter power and the development of technologies that make determining
Berman and Gierasch, 2021; UniProt Consortium, 2015), biomolecu- protein structures easier and faster. One example is the use of synchrotrons
lar pathway (Croft et al., 2014; Ogata et al., 2000; Oughtred et al., 2021; (e.g., the Advanced Photon Source at Argonne National Laboratory) to
Wishart et al., 2020), and other databases readily accessible to researchers generate high-quality X-ray beams for use in protein X-ray crystallography.
worldwide. These data are useful in their own right and also support the Another is the development of methods to solve the structures of mem-
development and evaluation of computer models used in drug discovery. brane-bound proteins, such as ion channels and cell-surface receptors.
In parallel, exponential increases in computer speed, measured as These can be high-quality drug targets because a drug does not need to
the number of mathematical operations executed per second, have enter the cell to access them and because they regulate many cellular pro-
made more and more detailed molecular simulations feasible. Ideally, a cesses. However, their structures were virtually impossible to solve until
computational chemist could design a compound, hand the design to a methods were developed in recent years to grow three-dimensional crystals
medicinal chemist to synthesize, and the compound would prove to bind of them. Since at least the 1980s, the promise of advances in SBDD methods
the target with nanomolar affinity. When this level of accuracy becomes has inspired the founding of multiple companies.
feasible, one might go further and compute the affinity of a candidate The field of physical chemistry tells us how to compute the binding
drug to all known human proteins in order to check for unwanted inter- affinity of two molecules in water (Gilson and Zhou, 2007). Ideally,
actions. This level of accuracy is not possible today, but existing methods one could use numerical solutions of SchrÖdinger’s equation to obtain
have predictive value, and growing computer power may make this vision the electronic wave function for the compound, the target protein,
achievable in the coming years. and the aqueous solvent, for any given conformation of the system
Approaches to predicting the interactions of a small molecule with (i.e., given the Cartesian coordinates of all atoms). From the wave func-
a protein may be broadly divided into ligand-based and structure-based tion, one could then compute the instantaneous force on every atom.
approaches, as explained below. Given this method of computing atomic forces, one could simulate the
system at atomistic detail, computing the reversible work of gradually
Using Chemical Similarity to Discover pulling the compound out of the protein binding site as all the atoms
wiggled, jiggled, and shifted due to thermal motion (Feynman et al.,
Targeted Ligands 1963). This reversible work would equal the free energy of binding, DGo,
If the targeted protein is an enzyme with a small-molecule substrate which is directly related to the dissociation constant, KD:
or a receptor for a small-molecule transmitter (e.g., histamine), then
compounds chemically similar to the substrate or transmitter may be ∆ G o = RTlnK D (Equation 1–1)
active against the target and thus useful starting points for drug design
(Figure 1–2). For some targets, more extensive information about ligands This would be a prohibitively massive calculation with existing com-
for the target may be available from prior drug discovery efforts and may puter technology. However, researchers have created fast approximations
be used to guide a new project. As noted above, even if a drug has already to such an ideal calculation, each with its own strengths and weaknesses
been developed against the target, there may still be room for a me-too in terms of accuracy, range of applicability, and the computer power
drug with better properties, such as less frequent oral dosing or reduced required (Figure 1–5).
side effects. Large quantities of data to support this ligand-based drug dis- An important approximation used in molecular modeling is the
covery approach are available in the scientific literature, patents, and public force field or potential function, a mathematical model for the atomic
databases (Gaulton et al., 2012; Gilson et al., 2016; Kim et al., 2019). forces that can be evaluated orders of magnitude faster than solving
Metrics of chemical similarity abstract the detailed chemical structures SchrÖdinger’s equation (Dauber-Osguthorpe and Hagler, 2019). Force
of compounds into characteristics that can be computed and compared fields often contain adjustable parameters fitted to give agreement with
across molecules. One approach computes a compound’s molecular reference solutions of SchrÖdinger’s equation. With a force field in hand,
fingerprint, which indicates whether various molecular substructures are it becomes practical to use molecular simulations to estimate protein-
present (Muegge and Mukherjee, 2016). Other similarity metrics jetti- ligand binding free energies (Tembe and McCammon, 1984; Kollmann,
son such details and, instead, compute and compare the overall shapes 1993; Gilson et al., 1997; Simonson et al., 2002). Such free energy methods
of the two molecules and the electrical fields they generate (Bajorath, are among the most accurate approaches available to predict protein-li-
2017). In a third approach, even molecular shape is set aside, and one gand binding affinities (Schindler et al., 2020), and their use by the drug
10 A. Statins
O OH O OH O OH O OH
HO HO HO HO
O OH OH OH OH
OH F F
F
N
N
O N
O
HN
Mevastatin Fluvastatin Cerivastatin Atorvastatin
B. SGLT Inhibitors
SGLT IC50 (nM) IC50 (nM) Relative selectivity

HO OH OH
inhibitor at SGLT1 at SGLT2 for SGLT2 (col2/col3)
Phlorizin 290 21 ~14
O O
HO O Canagliflozin 710 2.7 ~260
HO OH Dapagliflozin 1400 1.2 ~1200
OH Empagliflozin 8300 3.1 ~2700
Phlorizin
Ertugliflozin 2000 0.9 ~2200
F
Cl O
S
O O
HO HO
HO OH HO OH
OH Canagliflozin OH Dapagliflozin
O O
Cl
Cl O
OH O
O O
HO
HO OH HO OH
OH Empagliflozin OH Ertugliflozin
Figure 1–2 Using chemical similarity to develop ligands. A. Statins. Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase),
the rate-limiting enzyme in cholesterol synthesis. These inhibitors are widely used to lower blood levels of cholesterol (see Chapter 37). Mevastatin is a natural
product that inspired development of the three FDA-approved statins shown here. Each compound has a polycyclic lower part linked to a common hydroxyacid
moiety, which can also exist as a cyclic lactone. B. SGLT inhibitors. Sodium-glucose cotransporters (SGLTs) facilitate glucose ingress in the gastrointestinal tract
(SGLT1) and the kidney (SGLT2). The natural product phlorizin inhibits both SGLTs to varying extents. Modifications of the phlorizin structure led to the four
FDA-approved relatively specific SGLT2 inhibitors, the gliflozins, shown here. Gliflozins reduce renal reabsorption of glucose, thereby lowering blood sugar
concentrations, and thus are used to treat type 2 diabetes (see Chapter 51). Each compound has a glucose moiety (except ertugliflozin, which has a glucose-similar
moiety), sensible for compounds that interact with transporters that bind glucose. Phenyl-containing moieties endow each inhibitor with varying activities against
each of the two protein forms, as shown in the table. Activities are given as IC50, the concentration of drug (nM) that reduces the transporter’s activity by 50%. Data
adapted from Fediuk et al. (2020) and Wright (2021).
discovery community has been enabled by the acceleration of molecu- Another computational approach, molecular docking (Guedes et
lar simulations on graphics processing units (GPUs) (Salomon-Ferrer al., 2014; Huang, 2010; Meng, 2011), is fast enough to substitute for
R, et al., 2013). Even with GPUs, though, the simulations are too slow (or supplement) a large-scale experimental high-throughput screen.
to replace an experimental high-throughput screen of millions of com- In docking, most or all of the protein is held rigid, and the software
pounds. Instead, simulations are most commonly used to help medici- tries a vast number of different locations and conformations—poses—
nal chemists decide which chemical variations on a promising starting of a small molecule in the target’s binding site, searching for the one
compound are worth synthesizing and testing. Fast molecular simula- that is lowest in energy and hence most stable. Because docking leaves
tions also are used to explore the various conformations that a protein out so many known contributions to the free energy of binding (e.g.,
can adopt. For example, if a simulation shows that a new binding pocket protein flexibility and entropy), the energy model usually must be
could form as a result of thermal protein motions, it may be possible to tuned against experimental binding data to make it more predictive.
design a drug that will bind this hitherto unrecognized site. The resulting model is often called a docking score, to differentiate

A. Screening based on concepts of chemical similarity 11
Compound Library Known Ligands
SECTION I
Similar?
GENERAL PRINCIPLES
Candidate ligands
Optimization
(Med chem, Assay
crystallography, modeling)
Actives Potent drug candidates
B. Screening based on protein-ligand docking
3D structure of target
Compound database
(crystallography, NMR, modeling)
Protein-ligand docking
Favorable score?
Candidate ligands
Ligand optimization
Med chem, Experimental assay
crystallography, modeling
Ligands Drug candidates
Figure 1–3 Virtual screening. A. Virtual compound screening based on concepts of chemical similarity. Using available similarity metrics, the compounds in
a database (green) are computationally tested for chemical similarity to the known ligands (binders) of the targeted protein. Compounds that are above some
threshold similarity are considered candidate ligands and so are experimentally assayed for binding to the protein target. Those found to be inactive are set aside,
while “actives” are subjected to iterative rounds of ligand optimization where structure-activity relationships are defined and used to guide the design of new
compounds by medicinal chemists. When sufficiently active compounds are found, these become early-stage drug candidates. B. Virtual compound screening
based on protein-ligand docking. The compounds in a database (green) are computationally docked; i.e., optimally fitted into the binding site of a target protein of
known three-dimensional structure. Compounds whose computed stabilizing interactions with the binding site are above a threshold similarity are considered
candidate ligands and so are experimentally assayed for binding to the protein target. Those found to be inactive are set aside, while “actives” are subjected to
iterative rounds of ligand optimization. This typically involves using the protein structure to design new compounds that can form better interactions with the
binding site and solving crystal structures of the protein with selected compounds to determine whether the designed compounds bind as hoped and to guide
further rounds of chemical design and synthesis. Advanced computational methods, such as simulation-based free energy calculations, may also be used at this
stage. When sufficiently active compounds are found, these become early-stage drug candidates.

12
Figure 1–4 Crystal structure of the human immunodeficiency virus 1 protease (HIV-1 protease) with the protease inhibitor darunavir bound in the active site. Colored
tubes: protein backbone of the enzyme, a symmetric dimer made up of two identical subunits, where color indicates secondary structure (yellow, β-sheet; red,
α-helix; blue, turn; white, none). Translucent gray: overall surface of the protein, including both side-chain and backbone atoms. Ball and stick: darunavir in the
tunnel-shaped active site, with atoms colored by element (gray, carbon; red, oxygen; blue, nitrogen), with hydrogen atoms omitted for simplicity. Key hydrogen
bonds are shown as dashed green lines, and the oxygen of a water molecule that bridges between the drug and the protein is shown as a red ball. Atomic coordi-
nates from Protein Data Bank (Wang et al., 2011).
it from a true force field. Docking calculations are typically used for methods may be trained on existing data, such as on existing collections
virtual HTS (see Figure 1–3), in which thousands or millions of com- of protein–small-molecule binding data, the results of DELs, and protein
pounds in a chemical library are rapidly fitted into the binding site of structures, to enable direct prediction of protein–small-molecule binding
the targeted protein. Tens or hundreds of the top-scoring compounds and automated design of ligands for a targeted protein. They may also
may then be subjected to more detailed calculations or tested exper- support drug discovery in other ways, such as by predicting the three-
imentally. Although not all of the top-scoring compounds will be dimensional structures of proteins (AlQuraishi, 2021; Baek et al., 2021;
good binders, the fraction of binders will normally be enriched rel- Jumper et al., 2021), the energies of molecules as a function of confor-
ative to the chemical library as a whole. In addition, the predicted mation (Smith et al., 2017), and molecular properties such as whether a
binding poses may provide mechanistic insight and serve as starting compound is water soluble (Francoeur and Koes, 2021). Artificial intelli-
points for molecular simulations (Guest et al., 2022; Heinzelmann and gence and machine learning will undoubtedly play an expanding role in
Gilson, 2021). The empirically tuned scoring functions used in dock- drug discovery in the coming years.
ing can also be used to guide manual chemical editing of a known
binder with graphical molecular modeling software. For example, one
may manually edit an existing compound in the context of a three- Designing Large Molecules as Drugs:
dimensional rendering of the binding pocket to design a new com-
pound that reaches into a neighboring subpocket and forms stabilizing The Rise of Biopharmaceuticals
hydrophobic and hydrogen-bonding interactions with the protein. This Large molecules are increasingly important as therapeutic agents. For
interactive work may be aided by immersive visualization and manipu- example, antisense oligonucleotides are used to block gene transcription
lation technologies, such as virtual reality. or translation, as are siRNAs and modified mRNAs (as in several vaccines
for SARS-CoV-2 [severe acute respiratory syndrome coronavirus 2]).
Artificial Intelligence in Drug Discovery Important proteins used therapeutically include monoclonal antibodies,
Deep neural networks have proven their power in wide-ranging artifi- enzymes, and peptide hormones. Protein therapeutics were uncommon
cial intelligence tasks such as image recognition and language transla- before the advent of recombinant DNA technology except for the few
tion, and researchers are now exploring their use in drug discovery. These peptide hormones that could be isolated and purified in bulk. Insulin was

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— Baisse la tête, Aïeul : les branches vont faire tomber ton
casque !
— Aïeul à deux galons, as-tu reçu ma lettre ?
— Je l’ai reçue, Cang ; ne te fais plus de bile, vieux brave : justice
sera faite !
— Nous avons abominablement souffert, maître.
— Pourquoi, pourquoi nous avais-tu abandonnés ?
— Vois mes bras : ils sont bleus de coups de trique.
— Hé ! les porteurs ! faites attention aux écussons de la porte !
— Baisse la tête, Aïeul !
— Aux faisceaux, bavards !
En un clin d’œil, l’Aïeul se trouva remis en selle, et les tirailleurs
frémissants furent alignés, l’arme au pied, derrière leurs chefs de
section. Les deux officiers se serrèrent la main. La tête haute, les
yeux fixes, les dents claquantes, les talons réunis, l’adjudant Pietro
vit venir à lui le justicier.
— Vous viendrez à la chambre de détail aussitôt après la revue :
j’ai à vous parler.
— Oui… oui, mon lieutenant !
Annibal défilait en piaffant devant la double haie des baïonnettes
étincelantes et tout à coup la voix rauque de Hiên cria :
— Sauve-moi, Aïeul à deux galons, sauve-moi !… voilà que la
folie est revenue…
— Viens chez moi tout à l’heure, petit frère : je te guérirai.
Les salves de batteries ébranlaient les massifs qui
s’empanachaient de fumée blanche ; les drapeaux faisaient claquer
au-dessus des guirlandes et des palmes leur étamine tricolore. Les
pentes vertes de la montagne, les flamboyants écarlates, la baie
toute bleue où couraient des frissons d’argent, le ciel que ne souillait
nulle tache et d’où pleuvait la lumière triomphante saluaient de leur
sourire le retour de l’Aïeul.
Les clairons embouchèrent leurs cuivres rutilants, gonflèrent
leurs joues et soufflèrent. Derrière eux, Annibal dansa, avec des
craquements de cuirs neufs. La compagnie développa les quatre
anneaux de ses quatre sections ; les salaccos miroitèrent, les
baïonnettes lancèrent des éclairs ; le village entier suivit sur les
talons de la dernière file, pêcheurs brunis et couturés, costumés
d’étoffes teintes au cu-nao, bûcherons maigres et voûtés à force
d’avoir courbé leur échine sur les troncs abattus, notables
enturbannés de blanc et solennels dans leurs tuniques flottantes,
boys rasés et tondus à l’européenne balançant dans leurs doigts
chargés de bagues des cannes à pommes d’or, femmes de tirailleurs
trimbalant sur leurs hanches rebondies des marmots barbouillés de
vermillon, Chinois en veste lilas, en pantalons de soie blanche
ficelés au-dessus des babouches à semelles de feutre, gamins
farceurs vêtus chichement d’une culotte sans fond et d’une amulette
dansant au bout d’un cordon.
Devant le portail du télégraphe anglais, que des bougainvillias
violets encadraient, cinq ou six grands garçons blonds et roses
levèrent leurs casques plats à puggaree tissé de fils d’or.
— Bonjour, lieut’nant !
— Bonjour, monsieur White ! Bonjour, monsieur Beattie !…
Le pilote haut sur jambes et bourru qui savourait son manille
devant un mur où serpentaient des dragons émaillés salua de la
main le jeune camarade revenu de la brousse. Sous les vérandas à
grillages verts, des peignoirs bleus esquissèrent de courtes
révérences. Les gardiens du Phare descendus de leur cage vitrée,
Provençaux foncés et dépoitraillés, abandonnèrent les tables de
marbre rondes que les verres d’absinthe tachaient de vert trouble,
pour serrer dans leurs grosses pattes velues la main gantée :
— Bonne promenade, hein ?
— Merci ! bon apéritif !
— On vous attend pour le prendre, hein ? On va dire à la
patronne de le faire chauffer, té !
L’élégant comptable étalait complaisamment, sous les tritons qui
surmontaient la porte du Sanatorium, son smoking de toile à revers
de soie crème, son plastron de « zéphir » saumon et ses escarpins
vernis. Ce mulâtre, « intellectuel » que le lycée de la Pointe-à-Pitre
avait nanti de brevets douteux et que les lois de la métropole
bienveillante avaient dispensé de tout stage sous les drapeaux, était,
bien entendu, antimilitariste. Au passage de la « brute galonnée »,
du « buveur de sang », qui chevauchait à la tête d’une cohorte de
soudards, il eut une moue méprisante. Elle s’effaça de son visage
comme l’ombre d’un nuage sur une mare : Hiên le Maboul le frôlait
de son coude dur. Il lut la menace dans les yeux fous du tirailleur et
recula d’un pas : il se cogna au tronc moussu d’un lilas du Japon qui
badigeonna traîtreusement de vert tendre le smoking immaculé.
Un garçonnet repoussé par les serre-files bondit à pieds joints
dans une flaque d’eau : la boue liquide et rouge acheva l’œuvre de
la mousse ; des larmes hideuses constellèrent le pantalon raide,
amoureusement repassé, la ceinture de toile à boucle nickelée et à
bourse de cuir fauve, le plastron mou, le faux col à reflets de
porcelaine.
Le garçonnet s’esquivait ; les rires narquois des congaï, des
Chinois hilares, des sampaniers ricaneurs insultèrent à la douleur de
la victime : car l’Annamite n’aime point le sang-mêlé, qu’il désigne du
nom injurieux de chà-và (nègre).
Le comptable maudit ces braillards imbéciles dont le goût pour
les cérémonies militaires lui valait une douche d’eau boueuse. Il
disparut, poursuivi par les huées.
Annibal fit le beau, pointa, rua, afin d’éblouir ses congénères
attelés, deux par deux, aux victorias qui stationnaient devant le
perron de l’Hôtel Ollivier. Des fillettes anémiques, arrachées par le
clairon à leurs tas de sable, accoururent de toute la vitesse de leurs
maigres jambes brûlées. S’agriffant aux dossiers des bancs verts,
elles dansèrent de joie et leurs voix pointues chantèrent avec les
cuivres rugissants les vieux refrains nationaux.
La route cessait de courir en bordure de la plage, s’enfonçait
entre deux haies de lauriers-roses et de cactus que dominaient les
toits sombres des villas et les pentes raides de la montagne proche.
Les basses branches des tamariniers formaient une voûte épaisse
où se répercuta la clameur joyeuse de la foule. Un nouveau
contingent de Chinois et de congaï accourus du marché grossit la
colonne.
On arrivait à Benh-Dinh. Derrière les grilles de fer forgé, les
façades roses des bâtiments militaires ouvraient leurs larges baies :
bâtiments du Commissariat noyés dans l’ombre violette des
jaquiers ; Direction d’artillerie, où des piles de traverses peintes au
minium gisaient dans des massifs d’iris ; casernes d’artillerie, où
chantaient des trompettes nasillardes ; casernes d’infanterie que
revêtait encore la hideuse carapace des échafaudages.
Les serre-files coururent, pourchassèrent les gamins ; les
sections se formèrent en ligne les unes derrière les autres et la
compagnie ainsi massée fit son entrée sur l’esplanade ensoleillée
que bordait la forêt ombreuse. Les officiers d’artillerie campés sur
leurs mulets massifs abaissèrent, pour rendre son salut à l’Aïeul,
leurs lattes courbes ; derrière eux, les conducteurs indigènes firent
des signes d’amitié à leurs camarades tirailleurs. Les troupiers
d’infanterie coloniale, joignant les mains sur les croisières de leurs
baïonnettes, louèrent la tenue de la petite troupe qui se déployait, le
dos à la forêt, et s’alignait sans bruit.
En face de la haie des baïonnettes, l’autre lisière se garnissait de
casques blancs, de robes claires, de tuniques flottantes et pâles, de
chapeaux coniques, d’ombrelles à fleurs éclatantes. Les trompettes
fredonnèrent des notes pleurardes, les clairons chantèrent
allègrement ; un officier galopa dans le sable que les sabots de son
mulet puissant firent jaillir en gerbes d’étincelles ; il leva son sabre et
cria des commandements.
Un colonel passa au trot, puis se posta près des tribunes, et
devant lui défilèrent les petits canons poussiéreux, les pesants
fantassins et les tirailleurs alertes et sautillants. La revue était
achevée.
*
* *
— Rentrez dans votre chambre et n’en sortez plus. Le sergent-

major assurera votre service, en attendant que le chef de corps
envoie des ordres. Je vous préviens que je compte lui adresser une
lettre le mettant au courant des faits et demandant votre renvoi à
Saïgon.
Ainsi parla l’Aïeul. Pietro salua, fit demi-tour et gagna la porte.
Les tirailleurs, qui décrassaient leurs mousquetons sous la véranda,
le virent passer, blême et effaré, et connurent que son règne était
fini.
Dans la chambre de détail que tapissaient les contrôles
nominatifs, les synoptiques et les tableaux de service, les deux
officiers restaient seuls.
— A quoi songez-vous ? demanda l’Aïeul au sous-lieutenant.
— Je songe à tout ce mal que j’ignorais et que j’aurais pu
empêcher.
— Vous ne pouviez pas savoir. Vous êtes tout jeune, vous sortez
à peine de l’École, j’aurais dû vous avertir. Pietro, frappant du talon
et tendant le jarret, vous a convaincu aisément de ses vertus
militaires. Vous n’avez pu deviner l’âme vile qui se cachait sous ces
dehors de « parfait adjudant » ; vous avez eu confiance en lui, vous
vous êtes reposé sur lui du soin de maintenir la discipline intérieure ;
vous savez maintenant comment cette brute a manié le sceptre que
vous lui laissiez. Vous connaîtrez, quelque jour, le tort immense que
font à l’armée ces soi-disant « bons serviteurs » que nos troupiers
désignent de cette appellation caractéristique : « chiens de
quartier ».
— J’ai eu des torts, moi aussi. J’aurais dû, comme vous, me
rapprocher du tirailleur, lui inspirer confiance, étudier son âme. Mais,
cette fois encore, j’ai été abusé : tant de livres affirment que
l’Annamite est impénétrable, tant de fois Pietro m’a répété : « Ces
gens-là, on ne sait jamais ce qu’ils ont dans le ventre !… » J’ai fini
par me laisser persuader. J’ai cru avec tout le monde que l’Annamite
était menteur et dissimulé.
— Il l’était vraiment pour vous. La ruse est l’arme des faibles :
l’Annamite est faible et méfiant. Ses mandarins l’écrasaient ; les
conquérants n’ont pas réussi encore à le convaincre de sa
délivrance, parce qu’il s’est trouvé chez les conquérants des
hommes comme Pietro qui ont remis en vigueur les procédés
d’administration des mandarins. Il continue à ruser, mal guéri de sa
méfiance séculaire ; il refuse de livrer son âme, que masquent son
visage impassible devant le cadeau comme devant l’outrage, ses
yeux bridés. Derrière le masque, il souffre et se réjouit suivant
l’heure, comme un animal raisonnable, comme nous. Efforcez-vous
de l’apprivoiser, soyez immuablement bon et juste, et son âme
enfantine s’ouvrira, vous livrera ses prétendus secrets. Vous
découvrirez ce que j’ai découvert, que l’Annamite est un enfant
timide et bon, un peu craintif, mais qui ne demande qu’à se laisser
apprivoiser. Vous serez le père de cet enfant.
— Ou son Aïeul !
— Ou son Aïeul, dit le lieutenant en riant. Allons déjeuner : la
revue m’a creusé terriblement.
*
* *
Bèp-Thoï dispose sans bruit sur la nappe raide la tasse de café,

la pipe, le pot à tabac où sont taillés dans le bambou des mendiants
grimaçants et des bonzes difformes. Hiên le Maboul s’est agenouillé
près de l’Aïeul, a posé sa tête sur le genou du maître et parle d’une
voix étouffée et rauque :
— Tu as trop tardé ! tu as trop tardé !… La folie est rentrée en
moi. Je me suis débattu, j’ai lutté avec désespoir, mais tu n’étais plus
là pour me garder et m’encourager, et je t’ai cherché en vain… La
folie est rentrée dans mon âme que la terreur habitait, dans mon
corps déchiré par les coups de bâton : je suis fou !…
— Calme-toi ! dit l’Aïeul. Ta tête est encore faible et la frayeur l’a
troublée. L’adjudant va s’en aller et, dans quelques jours, tu seras
aussi gai, aussi tranquille, aussi peu tourmenté qu’avant mon départ.
— Oui ! Aïeul vénérable, je guérirai, je veux guérir ! Déjà tes
paroles me font du bien. Mais ce n’est point la peur seule qui me
rend fou…
— Dis-moi toute ta peine, petit frère.
— Je n’ose…
— Qu’est-ce que tu crains ? ne suis-je pas ton Aïeul ?
— Maître, maître, Maÿ m’a volé mon cœur et joue avec, comme
le chat joue avec le moineau ! Et je souffre parce que je l’aime, et,
chaque jour, je perds davantage la tête. Je suis jaloux !… Loin de
Maÿ, je suis inquiet, je redoute des choses hideuses ; et je cours
vers elle. Près de Maÿ, je ne suis pas heureux : elle répond à mes
questions par des railleries, par des allusions à ma pauvreté, à ma
sottise incurable ; mes paroles d’amour provoquent son rire
méchant ; mes menaces lui font hausser les épaules… Alors des
soupçons me viennent, que je ne puis dire, même à toi, vénérable
Aïeul, et, pour en finir avec la torture, je suis tenté de tuer le
bourreau.
— Voilà qui est plus grave !… Encore faudrait-il, avant de méditer
des mesures aussi radicales, qu’un indice quelconque fût venu te
dénoncer la trahison. As-tu surpris quelque chose ?
— Non !… je ne sais pas… je soupçonne…
— C’est parfait : tu es un imbécile !… Ta pauvre cervelle est
peuplée de fantômes grotesques et de monstres ridicules, qu’elle a
créés de toutes pièces et devant qui tu trembles. Tu es un imbécile !
— C’est vrai, vénérable Aïeul, appuie Bèp-Thoï, déposant sur la
table une boîte de cigares. Je ne suis pas instruit comme toi, mais je
suis vieux et la vie m’a enseigné des tas de choses qu’elle cache
aux jeunes hommes. Tout à l’heure, en étrillant ton cheval, j’ai dit à
Hiên qu’il était un imbécile de se mettre en tête de pareilles bourdes.
Il m’a regardé de travers et j’ai bien vu qu’il était irrité contre moi : les
jeunes gens d’aujourd’hui ne savent plus écouter patiemment les
discours utiles des anciens.
— Pourquoi n’as-tu pas écouté les sages paroles de Bèp-Thoï ?
continue l’Aïeul. Il a dit vrai : tout le mal vient de ton imagination. Ne
te figure pas, du reste, que tu es seul à souffrir de ce mal : tous les
hommes que le désir d’une femme affole sont, comme toi, torturés
de soupçons insensés et de visions idiotes. Mais le remède est aisé
à trouver, et, dans le cas présent, nous ne tarderons guère à
l’appliquer : c’est le mariage. Dans un mois, ce sera une affaire
réglée ; dans un mois, le fol amoureux se transformera subitement
en un mari épanoui et satisfait, soucieux uniquement, en rentrant au
logis, de ne point sentir l’odeur du riz brûlé qui empeste
fâcheusement la case, un mari comme tous les maris, sûr de lui-
même et d’autrui… Lève-toi, Hiên ; jure-moi que tu surveilleras ton
imagination, que tu n’écouteras plus ses calembredaines, que tu ne
seras plus jaloux enfin, ni fou.
— J’essaierai, vénérable Aïeul, j’essaierai.
— Tâche de ne pas oublier ta promesse… Quelle heure est-il,
Bèp-Thoï ?
Le vieux tirailleur considère attentivement le cadran d’une
formidable montre de nickel, extirpée de sa ceinture :
— Il est entre deux et trois heures, déclare-t-il, après mûr
examen de l’unique aiguille noire qui a survécu par miracle, malgré
les longues années de service de l’instrument.
Cette approximation paraît insuffisante à l’Aïeul qui allonge le
bras vers le dolman accroché au dossier d’une chaise :
— Il est trois heures moins le quart. Impossible de faire la sieste
maintenant. Allons voir la fête.
*
* *
Au bord de la plage, où grouillent les turbans noirs, les mouchoirs

roses, les crânes tondus et couronnés de tresses huileuses, les voix
suraiguës des enfants en liesse couvrent le chant de l’écume et des
galets. Un mât horizontal, lisse et bien savonné, que des cordes
amarrent aux planches de l’appontement, s’allonge au-dessus de
l’eau profonde. Un adolescent nu et râblé s’avance à pas hésitants
sur la poutre branlante et glissante, les bras en croix et les yeux
dirigés vers le drapeau dont la hampe est plantée dans un anneau
de fer, au bout du mât. Il s’efforce de ne point voir l’eau
tourbillonnante qui fuit sous ses pieds, mais elle attire invinciblement
son regard, le fascine, une seconde, et, pendant qu’il s’évertue à
garder son équilibre, balançant les paumes et creusant les reins, la
clameur de la foule pronostique déjà sa chute inévitable. Il chancelle,
tombe avec un juron, et la vague se referme sur lui. Il émerge,
crachant l’eau salée par le nez et la bouche, vomissant des injures
indistinctes en réponse aux huées de la populace. Un autre
adolescent s’achemine gauchement vers le drapeau qui flotte,
ironique.
Des nageurs s’époumonnent à poursuivre d’insaisissables
canards, qui tantôt plongent, montrant le duvet argenté de leur
ventre, tantôt filent au ras des vagues, battant des ailes et ramant
des pattes. Des nacelles de rotin tressé et calfaté se rangent en
ligne ; la pagaye aux mains, penché en avant, l’unique rameur guette
les gestes du fonctionnaire français qui lève son mouchoir. Le
mouchoir s’abaisse : les palettes des pagayes trouent l’eau et les
petites barques s’éloignent, à bonds furieux, vers la bouée tricolore
qui marque le but. Plus d’un concurrent maladroit paye d’un
plongeon inattendu quelque embardée trop hardie.
L’Aïeul, assis sur une roche que rembourrent des algues sèches,
considère en fumant sa pipe les ébats des jouteurs, et les cimiers
scintillants des salaccos formant derrière lui une haie compacte. Il
songe que les affiches municipales de France promettent pour le 14
juillet des réjouissances absolument analogues, et l’enthousiasme
des indigènes lui remet en mémoire la joie bon enfant du populaire
français. Les accordéons des bals publics, les orgues des chevaux
de bois nasillent à ses oreilles qui se souviennent. Mais son âme
claire et bien portante ne ressent aucune souffrance, à ce rappel de
la patrie absente. La Cochinchine, terre d’exil, lui paraît infiniment
préférable à la « douce » France. Il revoit, sous un ciel gris et
maussade, des rues étroites, pavées de cailloux inégaux et noirs,
bordées de hautes façades mélancoliques, des trottoirs suintants où
déambulent des gens hideux, bouffis, mal bâtis, des gens dont les
yeux crient l’envie et l’ennui ; et il se réjouit du peuple gai et bariolé,
criant sous le ciel lumineux.
Hiên le Maboul et Bèp-Thoï, las d’être heurtés et bousculés par
la populace remuante et braillarde, ont pris place sur la banquette
d’un restaurateur. Ils ont nettoyé plusieurs soucoupes de vermicelle
au gingembre, vidé un nombre incalculable de tasses de thé et bu
plusieurs petits verres de choum-choum. Le jeune tirailleur boit sans
entrain, cherche à s’étourdir, à se persuader qu’il lui sera facile de
tenir ses promesses de sagesse ; l’ancien, que des mois passés
dans la brousse et la chaleur de l’après-midi ont altéré, tarit son
verre sans y penser et, l’alcool aidant, devient merveilleusement
prolixe et abonde en réminiscences. Ce « Quatorze juillet » lui
rappelle beaucoup d’autres fêtes pareilles auxquelles il lui fut donné
d’assister :
— Moi qui te parle, j’ai vu des choses que tu ne soupçonnes
même pas, que tu ne verras jamais. En 1900, moi et quelques
autres vieux à médailles, montions la garde au Champ-de-Mars, à
l’Exposition, à Paris, en France. La consigne était d’empêcher de
fumer. Il arrivait de gros hommes en noir qui fumaient des cigares.
Jamais je n’osais parler à ces beaux messieurs, qui ressemblaient à
des mandarins ; mais, plus loin, ils rencontraient de hauts tirailleurs
nègres qui n’avaient pas peur comme moi. Ces grands diables
attrapaient les cigares, les jetaient par terre et marchaient dessus…
Tout ça, c’est des souvenirs comme peu de gens en ont : tu
comprends, après cela, que des pitreries comme celle-ci me laissent
froid. J’ai vu mieux… Hein, qu’en dis-tu ?… Tu ne m’écoutes pas,
mon garçon ?
Mécontent, le vieux grognard réclame du débitant une nouvelle
rasade. La tasse aux doigts, il grogne interminablement :
— J’avais raison tout à l’heure de dire à l’Aïeul que la jeunesse
d’aujourd’hui méprisait les avis des hommes mûrs. Elle ne sait
même point marquer de l’intérêt aux souvenirs merveilleux dont les
aînés peuvent régaler ses oreilles. Pendant que je cause, que je me
dessèche la langue, ce polichinelle me tourne presque le dos et
s’intéresse aux ébats de quelques hurluberlus qui se donnent du mal
pour faire du bruit. Que diable peut-il apercevoir de si absorbant ?
Des gamins qui tombent dans l’eau en beuglant, des sampans qui
culbutent : en voilà assez pour faire rouler à ce grand niais des
prunelles ahuries et inquiètes… Tiens, voilà Maÿ. Mâtin ! la
magnifique tunique noire et qui commence à se tendre agréablement
sur le devant !… Le derrière n’est pas mal non plus : ça gonfle et ça
remue !… Allons ! un coup de reins et une œillade pour l’Aïeul !… Il
ne te voit pas, ma fille, et j’ose dire qu’il s’en fiche. Un sourire au
beau jeune homme couleur kaki, en smoking à revers !… Il rend à la
main, celui-là… Ouvre l’œil, Hiên !… Il l’ouvre, le gaillard, et de
manière inquiétante… Eh ! petit frère, tu as l’air de souffrir ! Ça ne va
pas ?
Hiên le Maboul ne dit mot. La brise qui souffle de l’estuaire et lui
apporte les relents de corylopsis envolés du mouchoir de Maÿ
balaye jusqu’au souvenir de ses promesses. La tête lui fait mal, et le
cœur. Devant ses yeux égarés, tout flageole, se brouille et s’efface ;
à ses oreilles, la rumeur populaire ne parvient plus. La jalousie
l’étreint ; il souffre en silence.
— L’alcool ne te vaut rien, proclame Bèp-Thoï ; te voilà gris dès le
second verre !
XIX
Les travaux reprirent… De nouveau, les chansons et les

marteaux des charpentiers sonnèrent sous les hangars étayés. La
fourmilière des bûcherons s’égrena sur la route qui s’enfonçait dans
la forêt noircissante. Les couvreurs découpèrent au-dessus des toits
leurs silhouettes de singes babillards et brandissant des gerbes de
paille. De nouveau, les bois durs gémirent sous la dent des scies,
sous le tranchant des haches, ouvrirent avec des cris de colère leurs
muscles compacts aux tarières brutales. Les manœuvres
pataugèrent bruyamment dans la fosse à torchis, imitant le
dandinement grotesque des buffles enlizés et répondant par des
rires aux allocutions joyeuses que leur adressait leur chef d’équipe.
Des groupes de spectateurs badauds et bavards s’accroupirent en
files sur les talus du chemin.
Sous l’effort des wagonnets chargés, les rails retrouvèrent leur
brillant d’acier neuf, étincelèrent entre les épis jaunes. Le marécage
recula encore, envahi par le sable écroulé des bennes.
La joie affermissait les bras et les épaules lasses, rafraîchissait
les poitrines ruisselantes de sueur, et, malgré le dur soleil embrasant
les rizières, manœuvres, terrassiers, menuisiers, charpentiers,
maçons, bûcherons, couvreurs conservaient assez de souffle pour
enchanter leur tâche d’un refrain ou d’un éclat de rire.
Seul, Hiên ne retrouvait point son entrain de jadis. L’idée fixe,
établie dans son cerveau, n’accordait plus au misérable amoureux
une minute de relâche ; elle creusait ses joues flasques, enfonçait
ses yeux sombres sous les arcades osseuses, secouait comme d’un
frisson de fièvre ses mains noires où bleuissaient les veines
saillantes. La tête basse, raidissant ses bras derrière la tôle
oscillante, il n’écoutait point les harangues véhémentes de Nho.
— Pourquoi fais-tu cette figure d’enterrement ? Que te manque-t-
il encore pour être heureux ? L’Aïeul est revenu et nous a déclaré
qu’il ne s’en irait plus désormais ; l’adjudant Pietro nous a quittés
sans espoir de retour ; les travaux ont repris. Nous sommes tous
gais comme des pinsons ; toi seul es triste. Qu’as-tu enfin ? Es-tu
malade ?
— Je ne suis pas malade, disait Hiên entre ses dents.
— Tu en as tout l’air pourtant. Tu maigris, tu as une mine de
papier mâché et de drôles d’yeux : ils ont toujours l’air d’apercevoir
quelque chose que nous autres ne voyons pas. Avec qui causes-tu
tout bas ? Est-ce avec les esprits ?
— Peut-être !
— Va-t’en chez Thi-Teu la guérisseuse : elle te délivrera des
mauvais esprits.
— Laisse-moi ! laisse-moi !
— Il y a des gens qui passent leur temps à se rendre malheureux
eux-mêmes, grognait l’autre, mécontent. Débarrassés d’un souci, les
voilà qui se forgent d’autres raisons de se ronger le cœur ?… Diable
de Maboul !
Tandis que ses camarades raclaient à grands coups la benne
retentissante, l’halluciné s’accroupissait sur les talons, la tête enfouie
dans les mains, écoutait le rire pointu de Maÿ tinter à ses oreilles. Et
les minces lèvres rouges, saignant dans le petit visage pâle qui se
dessinait devant les yeux clos du fou, s’entr’ouvraient pour des
révélations horribles :
— Regarde-moi, Hiên ! Pendant que tu t’échinais à pousser ton
wagon, le jeune homme à casque plat est venu rôder près de la
palissade. Il m’a fait un signe ; je l’ai suivi jusqu’à la maison rose que
recouvrent les bancouliers. J’ai fait tomber ma veste courte, dénoué
ma ceinture de soie verte, et ses mains ont pétri mon corps brun et
ferme, mes seins frémissants. Il m’a donné des piastres neuves.
Entends-les sonner, individu idiot !…
— Viens ici, Hiên ! cria l’Aïeul, un jour que le tirailleur rêvait ainsi
sur le remblai. Je vais t’apprendre une nouvelle qui te ravira
certainement. Le colonel t’octroie une permission de huit jours, sur
ma demande : tu as besoin de changer d’air et de changer d’idées.
Va dans ton village, parle avec la mer et la forêt ; écoute-les : elles
savent les paroles qui guérissent les cœurs malades, elles auront
pitié de toi qu’elles ont vu naître et grandir, qui connais leur langage.
Tu guériras. Va, petit frère !…
*
* *
La forêt compatissante ouvrit à l’enfant retrouvé ses clairières. Au

flanc des bambous noircis que le coupe-coupe avait tranchés, des
pousses nouvelles avaient jailli, vivaces et touffues. Les jeunes
roseaux que Phâm-vân-Hiên avait vu sourdre du gazon se
hérissaient d’épines tendres ; l’herbe drue avait submergé la pierre
plate dont il faisait jadis son oreiller. Aux troncs des banyans, des
lianes étaient mortes, lasses de l’attente ; d’autres avaient tapissé
l’écorce de leurs feuilles vernies, de leurs fleurs étoilées. Des plaies
fraîches saignaient sur les fûts pâles des gommiers.
Mais la forêt se souvenait : ses mille voix chuchotaient les
refrains d’autrefois sur le même ton. Hiên reconnut le rire éperdu de
la cascade raillant les roches éplorées dans leurs cheveux de
mousse, le babil mystérieux des roseaux rapprochant leurs têtes
nuageuses, le ronflement des crapauds-buffles hissés sur les
racines boueuses des palétuviers, l’appel rythmé des huppes,
l’hymne rageur des coqs, la plainte douce des tourterelles, le
gémissement des singes batailleurs.
— Je n’ai point changé, semblait dire la forêt, reste avec moi,
âme inquiète, reste avec moi… Baigne dans mes ruisseaux tes
pieds que les cailloux du chemin ont ensanglantés ; allonge sur mon
herbe molle ton corps brisé de fatigue. Ma rosée rafraîchira ton front
que la fièvre brûle ; l’émeraude de mes aubes, l’or de mes midis, la
pourpre de mes crépuscules chasseront de tes prunelles extasiées
les visions malsaines ; j’emplirai tes oreilles de mon chant
innombrable… Reste avec moi, pauvre âme affligée. Redeviens mon
enfant sauvage et instinctif, primitif et inconscient. La sagesse est
dans la contemplation de la nature. Regarde-moi, écoute-moi vivre.
Entends-tu ? une loutre a bondi hors des roseaux, troué l’eau noire
de la mare, qui se plisse de courtes vagues. Reconnais-tu le cri
saccadé du gecko, dont les griffes égratignent la branche du teck ?
Entre les buissons froissés un sanglier fuit, le groin levé, flairant la
brise qui lui apporta l’inquiétude. Un craquement d’os : un chat-tigre
plante ses incisives acérées dans l’échine frissonnante d’un rat
musqué. Le tigre, roi des marais, erre dans la brousse qu’épouvante
son aboiement enroué. Écoute-moi vivre, reste avec moi !…
Ainsi parlait la forêt maternelle. Toute la journée, Hiên l’écoutait,
assis dans la clairière où, tout enfant et adolescent, il tailladait les
bambous. Au crépuscule, blotti parmi les algues, il entendait la voix
grondante de la mer qui l’invitait de même à la sagesse :
— Vois mes amants, les pêcheurs. Apprends d’eux à vivre sans
autre amour au cœur que l’amour de mon visage éternellement
changeant, éternellement pareil. Installés autour de la voile qu’ils ont
déroulée sur le sable de la plage, ils tordent les cordages de rotin
que mes vagues ont rompus d’un coup d’épaule, remplacent par un
bambou neuf la vergue que mes tarets ont rongée. Écoute-les rire,
ces gens heureux, dont la civilisation n’a point déformé le cerveau et
compliqué la pensée. Après la rude journée de pêche, ils dormiront
sur le varech parfumé et mon hymne inlassable bercera leur
sommeil sans rêves. Viens à moi, pauvre être qui as voulu connaître
la vie et qui as souffert par elle, viens à moi : je te donnerai la paix
profonde que je dispense à mes amoureux, la paix profonde que
recèlent les flancs transparents de mes houles, la paix profonde dont
jouissent éternellement les noyés, allongés sur le fin gravier de mes
abîmes…
La nuit descendait sur les vagues frangées d’écume crépitante,
chassant Hiên le Maboul de la plage où tout à l’heure viendraient
s’ébattre les bêtes féroces. Il suivait à longues enjambées les ruelles
bordées de bambous où séchaient les filets. Derrière les jarres de
grès brun que remplissait la saumure, les enfants et les jeunes filles
le regardaient, les uns moqueurs et ricaneurs, les autres pitoyables
à la peine devinée sur le visage osseux. Dans la hutte minable que
secouait le vent, il s’accroupissait sur le lit de camp, où prenaient
place le père et la mère, ridés, ratatinés et bavards.
— Te voilà mis comme un mendiant ! grognait le père. La boue a
souillé ton pantalon et tes jambières, les ronces ont lacéré ton
turban… Tu n’as guère changé !
Et les mains noires du vieux tremblaient sur les baguettes,
nettoyant activement la soucoupe de riz.
Des notables entraient, buvaient une tasse de thé, considéraient
le tirailleur.
— Il a grandi et s’est élargi, constataient-ils, mais il n’est pas
devenu plus gai. Il semble qu’un chagrin le travaille.
— Laissez donc ! disait la mère, petite vieille criarde ; il a toujours
ses yeux de toqué, voilà tout.
Les notables hochaient la tête.
— La ville ne te vaut rien, disait le maître d’école. Tu es un enfant
de la brousse : hâte-toi de revenir vers la brousse. Ne laisse point
les femmes de la ville te voler ton cœur. Il y a des années, mon fils
est parti comme toi et je ne l’ai jamais revu. Des sampaniers m’ont
dit qu’une fille lui avait jeté un sort, qu’il s’était enfui avec elle. Le
maître d’école de Baria l’a vu, creusant un fossé, dans une rue de
Saïgon, sous le rotin des miliciens et des gardes-chiourme. Il est
mort, peut-être, maintenant… Prends garde, toi aussi ; méfie-toi des
sortilèges. Veille sur ton cœur !
Tous partaient enfin. Hiên le Maboul restait seul sur le lit de
camp, la nuque appuyée à l’étroit oreiller de paille. La forêt proche et
la mer proche lui parlaient avec le vent qui faisait danser les images
saintes sur les panneaux de papier rouge. L’oubli venait à lui avec
l’air froid, qui soufflait entre les planches disjointes : il se crut guéri et
fort.
— Je reviendrai vers vous, promettait-il au ressac, aux ramures
bruissantes, aux chouettes hululantes. Dans quelques mois, je serai
libre, et, durant ces quelques mois, votre souvenir et l’Aïeul me
sauveront de la folie. Vous me reverrez joyeux et le cœur en paix. Je
serai le bûcheron qui erre au petit jour dans les sentiers brumeux,
qui aspire de ses poumons rajeunis le parfum des feuilles humides.
Je serai le pêcheur campé sur le rouf des jonques décorées d’yeux
sanglants, le pilote qui pèse sur le cordage de rotin tressé et manie
du talon la barre du gouvernail taillé en forme de lyre. Je serai votre
enfant à toutes deux, votre enfant insouciant et ignorant des choses
humaines…
Il rejetait la couverture crasseuse, se dressait sur la natte où
couraient les cancrelats affairés et cuirassés d’acier bruni,
décrochait la hachette à tranchant étroit et rouillé, frottait de la
paume la poignée poussiéreuse. Il tirait d’un coffre en bois de
camphrier ses vieilles hardes déchirées et rapiécées qui fleuraient le
bétel et la bruyère. La vase des palétuviers étoilait l’étoffe rougeâtre
de larges taches noires ; les algues sèches la verdissaient ; la sève
des gommiers lustrait les manches que les palmiers d’eau avaient
griffées. Au fond de la caisse, dormait le vieux chapeau conique en
feuilles de latanier, délavé par la rosée et les pluies, crevé par les
branches basses.
Mais tandis que Hiên le Maboul, incliné vers le coffre en bois de
camphrier, remuait les reliques et les senteurs de son passé et se
persuadait de sa guérison, le souvenir de Maÿ revint à lui : Hiên
lâcha le couvercle, qui se referma sur les guenilles affaissées et
mortes, et serra les poings. Il vit la fillette, nue et rieuse, étendue, la
hanche en l’air, à côté de l’ennemi… La vision s’envolait aussitôt,
brève comme un éclair et, comme un éclair, aveuglante. Mais, dans
le cerveau du malheureux, dans ses tempes, dans ses oreilles, le
sang bourdonna. Il connut qu’il n’était point guéri et s’abattit sur sa
natte en geignant. Vainement l’appelèrent le vent, la houle, les
arbres désespérés.
A l’aube, il retourna vers la ville.
XX
— Guéris-moi, vieille mère ! gémit Hiên le Maboul.

— Guéris-le, répéta l’Aïeul. Il t’a dit son mal : son âme et son
corps souffrent.
Thi-Teu souffla sur la mèche du quinquet : la flamme dansa ; les
dorures des bouddhas enfumés s’avivèrent ; dans le visage osseux
et desséché de la vieille femme, les yeux s’illuminèrent entre les
paupières plissées. Les mains déformées se joignirent sur la poitrine
drapée d’étoffe blanche, les lèvres incolores murmurèrent des
invocations incompréhensibles. Au dehors, la nuit se peuplait de
lucioles errantes qui chatoyaient entre les fûts vagues des cocotiers.
La guérisseuse parla :
— Aïeul à deux galons, je ne puis oublier que tu as fait rebâtir ma
case détruite par l’incendie, que tu m’as protégée contre les bandits
qui m’accusaient de sorcellerie et voulaient me bannir du village. Je
ne puis oublier que je t’ai veillé aux heures de fièvre et que tu m’as
permis de t’aimer comme un fils. Je soignerai ton serviteur comme je
t’ai soigné. Les mauvais esprits sont en lui : je vais essayer de les
chasser.
Devant la table haute et étroite où se dressaient, parmi les
chandeliers de bois et les fleurs de lotus, le panneau sacré de teck
incrusté, Hiên le Maboul s’agenouilla et se prosterna, les coudes et
le front contre terre, les mains réunies en coupe sur la nuque ; trois
fois il se prosterna, puis s’immobilisa dans la poussière. Les
baguettes d’encens fumaient, le bronze tintait sous les coups
répétés du marteau de bois, les lèvres pâles de Thi-Teu
prononçaient avec volubilité des formules d’incantation. L’Aïeul
pensif s’éloignait entre les cocotiers. Les baguettes d’encens
s’éteignirent, la mélopée s’acheva. Hiên soupira, se leva :

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