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Seminar 1 From Pharmaceutical Chemistry I 02
Seminar 1 From Pharmaceutical Chemistry I 02
(medicinal)
chemistry
Introduction
PharmDr. Pavol Ježko, PhD.
Department of Pharmaceutical Chemistry
Faculty of Pharmacy, Comenius University
Odbojarov 10, 832 32 Bratislava, Slovakia
Tel: + 421 250 117 395
e-mail: jezko@fpharm.uniba.sk; p.jezko@gmail.com 1
1
Definition of pharmaceutical chemistry
• pharmaceutical chemistry
– discovery
– development
– identification and interpretation of the mode of action of
biologically active compounds at the molecular level
2
Drugs
• Organic (inorganic) compounds and biomolecules
(proteins, antibodies, …) that activates or inhibits the function
of a target with benefit to the patient
activity
(target binding place stereoelectronic compatibility)
4
Basic terms in pharmaceutical chemistry
• TARGET (biomacromolecule to interfere with)
• BINDING POCKET – ACTIVE SITE
(part of the target appropriate to bind a small ligand)
• PHARMACOPHORE (a part of a molecule that is recognized at a receptor site and is
responsible for that molecule's biological activity)
• LIGAND organic molecule possessing target affinity, that has to be stereo-
electronically compatible with binding pocket
ACTIVE is a compound detected by usually HTS
HIT is a active compound identified in a screen with confirmed structure and
activity, that need to be developed into lead compound
LEAD is a active compound with convenient properties: drug-likeness,
solubility, synthetic feasibility, patentability
DRUG CANDIDATE high activity, good selectivity, in vivo efficiency
DRUG after success in clinical trials approved by FDA, EMEA
• DRUG-LIKENESS complex properties
– (ADME/Tox: Absorption/Distribution/Metabolism/Excretion/Toxicity)
Drug development basic chronology
selection of disease (cardiovascular, autoimmune, infectious, hereditary, mental, cancer …)
9
Structure – activity relationship
• primary task of the medical chemist is to identify leading sceleton and its
subsequent modification in order to obtain a suitable candidate to drug that
may be introduced into clinical practice
• irrational approach: make all the easy and available variations of the leading
sceleton
11
Bioisosteric substitution
12
Classical bioisosters
• Are of similar size, shape and valence electron configuration
N X N
HO HO HO
H X = O, NR
Nonclassical bioisosters of Halogen
Halogen CF3 CN NCN2 C(CN)3
Nonclassical bioisosters of Urea-like 14
NHC(=S)NH2 NHC(=NCN)NH2 NHC(=CHNO2)NH2
15
Systematic screening
• systematic testing of new compounds without
the known mechanism of action and
pharmacological potential
18
Genetics, genomics
Genetics,
and drug development
• Over the last 15 to 25 years there has been progress in
several scientific fields, particularly combinatorial
chemistry, genomics, proteomics and bioinformatics,
which are promise for the future in a streamlining of
procedures discovering new drugs.
20
Computational
pharmaceutical chemistry
• Computational chemistry
– is a discipline using mathematical methods for the
calculation (computer-assisted) of molecular properties or
for the simulation of molecular behaviour
– most used methods
• quantum mechanics
• classical mechanics
• Necessary condition
– biological activity = f (3D structure + physicochemical
properties)
• Sufficient condition
– high-affinity ligand must exhibit also good pharmacokinetic
and toxicological properties
• pharmacokinetic ADMET (Absorption, Distribution, Metabolism,
Excretion and toxicity ) parameters
• (poor biopharmaceutical properties and toxicity are one of the
major reason for drug development failure)
22
Molecular modeling
and
medicinal chemistry
• Molecular modeling methods
– Quantum chemistry
– Molecular Mechanics
– Molecular Dynamics and Monte Carlo
23
Electronic structure methods
• semi-empirical methods (MNDO, AM1, PM3, ...)
– programs: MOPAC, HyperChem, Gaussian, ...
• ab initio methods
– Hartree-Fock methods
– electronic correlation methods
• Moller-Plesset Pertubation Theory (MP2, MP3, MP4, MP5)
• Hybrid methods
– ONIOM, QM/MM approaches
– Programs: Gaussian, Jaguar,...
• CADD (Computer
(Computer--Assisted Drug Design)
Design)
was developed by applying methods and
theories of computational chemistry to study
the properties of drugs
25
Computer-assisted drug design (CADD)
• Computer-assisted drug design
– involves all computer-assisted techniques used to discover, design and optimize
biologically active compounds with a putative use as drugs
• CADD is the science and art of finding molecules of potential therapeutic value that
satisfy a whole range of quantitative criteria such as high potency, high specificity,
minimal toxic effect and good bioavailabity
• CADD implies the use of computer graphics to visualize and manipulate chemical
structures, to synthesize “ in silico “ new molecules, to determine their
conformation, and to assess the similarities aind dissimilarities between series of
molecules
• CADD also involves the calculation of the interaction energy between drug
molecules and hypothetical or experimentally determined macromoleculas
structures
26
Computer assisted drug design
AIM:
• to discover, enhance, study biologically active molecules that will bind
to a selected target and if so how strongly before a compound
is synthesized
Do we Do we
know 3D know 3D
structure structure
of homolog
?
protein?
SBDD LBDD
What What
compound compound
? ?
32
EGFR inhibitor gefinitib (IRRESA)
(approved for refractory lung cancer, AstraZeneca)
EGFR (ErbB, HER1) tyrosine kinase receptor: abnormal or over-expressed in the breast, lung,
brain, prostate, gastrointestinal tract, ovaries cancer. EGFR is a receptor for EGF proteins (1986
Nobel Prize). Upon activation by its growth factor, EGFR forms active homodimer possessing
intracellular TK activity that initiate several signal transduction cascades leading to DNA
synthesis and cell proliferation. Gefitinib inhibits EGFR by binding to the ATP-binding site.
Thus receptor and therefore also malignant cells are inhibited.
4-anilinoquinazoline SAR optimized main metabolic products I, II both met. routes
Lead I, good in vitro activity, in vivo blocked
hampered by rapid metabolism
Cl- similar in size and lipophilicity as Me- group
caused by cytochrome P450
F- almost the same size as H- (no steric effect)
enzymes
both groups are resistant to oxidation, better in vivo
activity, pharmacokinetic properties improved by
morpholino group, because of basic nitrogen that
enhanced water solubility
What should compound fulfill to become a drug?
Chemical Space
Lead-like Drug-like
Chem Space: 1060 -10200 Drugs
DB of 11 atoms C,N,O, F: 26 400 000 stable
compounds (110.9 M if stereoisomers included)
J.-L. Reimond J. Chem. Inf. Model. 47, 2007, 342.
Bioavailability
• (in vitro) active compound, to perform as drug, has to reach its target
in the human body (in vivo)
optimal water and fat solubility logP (octanol / water) (intestinal lining, aqueous
blood, penetrate cellular membrane to rich inside the cell) The distribution
coefficient (Log D) is the correct descriptor for ionisable systems. log D is pH
dependent (e.g. at pH = 7.4 is the physiological pH of blood serum)
Ertl, P. in Molecular Drug Properties, R. Mannhold (ed), Wiley-VCH , 2007, 111 – 126.
Ro5 determined from 2D tructure
http://www.molinspiration.com
Ertl, P. et al., J. Med. Chem. 2000, 43: 3714-3717. (molecular property prediction toolkit )
Ro5 violations
Absorption as f(PSA, LogP)
• logP
(membrane transport connected with fat and water solubility)
• log pKa
(influences binding Ki and also logP)