Medicinal chemistry

Medicinal or pharmaceutical chemistry is a

scientific discipline at the intersection of
chemistry and pharmacy involved with
designing and developing pharmaceutical
drugs. Medicinal chemistry involves the
identification, synthesis and development of
new chemical entities suitable for therapeutic
use. It also includes the study of existing
drugs, their biological properties, and their
quantitative structure-activity relationships
(QSAR).[1][2]

Medicinal chemistry is a highly

interdisciplinary science combining organic
chemistry with biochemistry, computational
Pharmacophore model of the benzodiazepine binding site
chemistry, pharmacology, molecular biology,
on the GABAA receptor
statistics, and physical chemistry.

Compounds used as medicines are most often

organic compounds, which are often divided into the broad classes of small organic molecules (e.g.,
atorvastatin, fluticasone, clopidogrel) and "biologics" (infliximab, erythropoietin, insulin glargine), the latter
of which are most often medicinal preparations of proteins (natural and recombinant antibodies, hormones
etc.). Medicines can also be inorganic and organometallic compounds, commonly referred to as
metallodrugs (e.g., platinum, lithium and gallium-based agents such as cisplatin, lithium carbonate and
gallium nitrate, respectively). The discipline of Medicinal Inorganic Chemistry investigates the role of
metals in medicine (metallotherapeutics), which involves the study and treatment of diseases and health
conditions associated with inorganic metals in biological systems. There are several metallotherapeutics
approved for the treatment of cancer (e.g., contain Pt, Ru, Gd, Ti, Ge, V, and Ga), antimicrobials (e.g., Ag,
Cu, and Ru), diabetes (e.g., V and Cr), broad-spectrum antibiotic (e.g., Bi), bipolar disorder (e.g., Li).[3][4]
Other areas of study include: metallomics, genomics, proteomics, diagnostic agents (e.g., MRI: Gd, Mn; X-
ray: Ba, I) and radiopharmaceuticals (e.g., 99mTc for diagnostics, 186 Re for therapeutics).

In particular, medicinal chemistry in its most common practice—focusing on small organic molecules—
encompasses synthetic organic chemistry and aspects of natural products and computational chemistry in
close combination with chemical biology, enzymology and structural biology, together aiming at the
discovery and development of new therapeutic agents. Practically speaking, it involves chemical aspects of
identification, and then systematic, thorough synthetic alteration of new chemical entities to make them
suitable for therapeutic use. It includes synthetic and computational aspects of the study of existing drugs
and agents in development in relation to their bioactivities (biological activities and properties), i.e.,
understanding their structure–activity relationships (SAR). Pharmaceutical chemistry is focused on quality
aspects of medicines and aims to assure fitness for purpose of medicinal products.[5]

At the biological interface, medicinal chemistry combines to form a set of highly interdisciplinary sciences,
setting its organic, physical, and computational emphases alongside biological areas such as biochemistry,
molecular biology, pharmacognosy and pharmacology, toxicology and veterinary and human medicine;
these, with project management, statistics, and pharmaceutical business practices, systematically oversee
altering identified chemical agents such that after pharmaceutical formulation, they are safe and efficacious,
and therefore suitable for use in treatment of disease.

In the path of drug discovery

Discovery

Discovery is the identification of novel active chemical compounds, often called "hits", which are typically
found by assay of compounds for a desired biological activity.[6] Initial hits can come from repurposing
existing agents toward a new pathologic processes,[7] and from observations of biologic effects of new or
existing natural products from bacteria, fungi,[8] plants,[9] etc. In addition, hits also routinely originate from
structural observations of small molecule "fragments" bound to therapeutic targets (enzymes, receptors,
etc.), where the fragments serve as starting points to develop more chemically complex forms by synthesis.
Finally, hits also regularly originate from en-masse testing of chemical compounds against biological targets
using biochemical or chemoproteomics assays, where the compounds may be from novel synthetic
chemical libraries known to have particular properties (kinase inhibitory activity, diversity or drug-likeness,
etc.), or from historic chemical compound collections or libraries created through combinatorial chemistry.
While a number of approaches toward the identification and development of hits exist, the most successful
techniques are based on chemical and biological intuition developed in team environments through years of
rigorous practice aimed solely at discovering new therapeutic agents.

Hit to lead and lead optimization

Further chemistry and analysis is necessary, first to identify the "triage" compounds that do not provide
series displaying suitable SAR and chemical characteristics associated with long-term potential for
development, then to improve remaining hit series with regard to the desired primary activity, as well as
secondary activities and physiochemical properties such that the agent will be useful when administered in
real patients. In this regard, chemical modifications can improve the recognition and binding geometries
(pharmacophores) of the candidate compounds, and so their affinities for their targets, as well as improving
the physicochemical properties of the molecule that underlie necessary pharmacokinetic/pharmacodynamic
(PK/PD), and toxicologic profiles (stability toward metabolic degradation, lack of geno-, hepatic, and
cardiac toxicities, etc.) such that the chemical compound or biologic is suitable for introduction into animal
and human studies.

Process chemistry and development

The final synthetic chemistry stages involve the production of a lead compound in suitable quantity and
quality to allow large scale animal testing, and then human clinical trials. This involves the optimization of
the synthetic route for bulk industrial production, and discovery of the most suitable drug formulation. The
former of these is still the bailiwick of medicinal chemistry, the latter brings in the specialization of
formulation science (with its components of physical and polymer chemistry and materials science). The
synthetic chemistry specialization in medicinal chemistry aimed at adaptation and optimization of the
synthetic route for industrial scale syntheses of hundreds of kilograms or more is termed process synthesis,
and involves thorough knowledge of acceptable synthetic practice in the context of large scale reactions
(reaction thermodynamics, economics, safety, etc.). Critical at this stage is the transition to more stringent
GMP requirements for material sourcing, handling, and chemistry.

Synthetic analysis

The synthetic methodology employed in medicinal chemistry is subject to constraints that do not apply to
traditional organic synthesis. Owing to the prospect of scaling the preparation, safety is of paramount
importance. The potential toxicity of reagents affects methodology.[5][10]

Structural analysis

The structures of pharmaceuticals are assessed in many ways, in part as a means to predict efficacy,
stability, and accessibility. Lipinski's rule of five focus on the number of hydrogen bond donors and
acceptors, number of rotatable bonds, surface area, and lipophilicity. Other parameters by which medicinal
chemists assess or classify their compounds are: synthetic complexity, chirality, flatness, and aromatic ring
count.

Structural analysis of lead compounds is often performed through computational methods prior to actual
synthesis of the ligand(s). This is done for a number of reasons, including but not limited to: time and
financial considerations (expenditure, etc.). Once the ligand of interest has been synthesized in the
laboratory, analysis is then performed by traditional methods (TLC, NMR, GC/MS, and others).[5]

Training
Medicinal chemistry is by nature an interdisciplinary science, and practitioners have a strong background in
organic chemistry, which must eventually be coupled with a broad understanding of biological concepts
related to cellular drug targets. Scientists in medicinal chemistry work are principally industrial scientists
(but see following), working as part of an interdisciplinary team that uses their chemistry abilities,
especially, their synthetic abilities, to use chemical principles to design effective therapeutic agents. The
length of training is intense, with practitioners often required to attain a 4-year bachelor's degree followed
by a 4-6 year Ph.D. in organic chemistry. Most training regimens also include a postdoctoral fellowship
period of 2 or more years after receiving a Ph.D. in chemistry, making the total length of training range
from 10 to 12 years of college education. However, employment opportunities at the Master's level also
exist in the pharmaceutical industry, and at that and the Ph.D. level there are further opportunities for
employment in academia and government.

Graduate level programs in medicinal chemistry can be found in traditional medicinal chemistry or
pharmaceutical sciences departments, both of which are traditionally associated with schools of pharmacy,
and in some chemistry departments. However, the majority of working medicinal chemists have graduate
degrees (MS, but especially Ph.D.) in organic chemistry, rather than medicinal chemistry,[11] and the
preponderance of positions are in research, where the net is necessarily cast widest, and most broad
synthetic activity occurs.

In research of small molecule therapeutics, an emphasis on training that provides for breadth of synthetic
experience and "pace" of bench operations is clearly present (e.g., for individuals with pure synthetic
organic and natural products synthesis in Ph.D. and post-doctoral positions, ibid.). In the medicinal
chemistry specialty areas associated with the design and synthesis of chemical libraries or the execution of
process chemistry aimed at viable commercial syntheses (areas generally with fewer opportunities), training
paths are often much more varied (e.g., including focused training in physical organic chemistry, library-
related syntheses, etc.).

As such, most entry-level workers in medicinal chemistry, especially in the U.S., do not have formal
training in medicinal chemistry but receive the necessary medicinal chemistry and pharmacologic
background after employment—at entry into their work in a pharmaceutical company, where the company
provides its particular understanding or model of "medichem" training through active involvement in
practical synthesis on therapeutic projects. (The same is somewhat true of computational medicinal
chemistry specialties, but not to the same degree as in synthetic areas.)

See also
Chemistry portal

Science portal

Bioisostere
Biological machines
Chemoproteomics
Drug design
Pharmacognosy
Pharmacokinetics
Pharmacology
Pharmacophore
Xenobiotic metabolism

References
1. Davis A, Ward SE, eds. (2015). The Handbook of Medicinal Chemistry. Royal Society of
Chemistry. doi:10.1039/9781782621836 (https://doi.org/10.1039%2F9781782621836).
ISBN 978-1-78262-419-6.
2. Barret R (2018). Medicinal Chemistry: Fundamentals. London: Elsevier. ISBN 978-1-78548-
288-5.
3. Hanif M, Yang X, Tinoco AD, Plażuk D (2020-05-28). "Editorial: New Strategies in Design
and Synthesis of Inorganic Pharmaceuticals" (https://www.ncbi.nlm.nih.gov/pmc/articles/PM
C7270431). Frontiers in Chemistry. 8: 453. Bibcode:2020FrCh....8..453H (https://ui.adsabs.h
arvard.edu/abs/2020FrCh....8..453H). doi:10.3389/fchem.2020.00453 (https://doi.org/10.338
9%2Ffchem.2020.00453). PMC 7270431 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC72
70431). PMID 32548093 (https://pubmed.ncbi.nlm.nih.gov/32548093).
4. Anthony EJ, Bolitho EM, Bridgewater HE, Carter OW, Donnelly JM, Imberti C, et al.
(November 2020). "Metallodrugs are unique: opportunities and challenges of discovery and
development" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163330). Chemical Science.
11 (48): 12888–12917. doi:10.1039/D0SC04082G (https://doi.org/10.1039%2FD0SC04082
G). PMC 8163330 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163330).
PMID 34123239 (https://pubmed.ncbi.nlm.nih.gov/34123239).
 5. Roughley SD, Jordan AM (May 2011). "The medicinal chemist's toolbox: an analysis of
reactions used in the pursuit of drug candidates". Journal of Medicinal Chemistry. 54 (10):
3451–3479. doi:10.1021/jm200187y (https://doi.org/10.1021%2Fjm200187y).
PMID 21504168 (https://pubmed.ncbi.nlm.nih.gov/21504168).
6. Hughes JP, Rees S, Kalindjian SB, Philpott KL (March 2011). "Principles of early drug
discovery" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058157). British Journal of
Pharmacology. 162 (6): 1239–1249. doi:10.1111/j.1476-5381.2010.01127.x (https://doi.org/1
0.1111%2Fj.1476-5381.2010.01127.x). PMC 3058157 (https://www.ncbi.nlm.nih.gov/pmc/art
icles/PMC3058157). PMID 21091654 (https://pubmed.ncbi.nlm.nih.gov/21091654).
7. Johnston KL, Ford L, Umareddy I, Townson S, Specht S, Pfarr K, et al. (December 2014).
"Repurposing of approved drugs from the human pharmacopoeia to target Wolbachia
endosymbionts of onchocerciasis and lymphatic filariasis" (https://www.ncbi.nlm.nih.gov/pm
c/articles/PMC4266796). International Journal for Parasitology. Drugs and Drug Resistance.
Includes articles from two meetings: "Anthelmintics: From Discovery to Resistance", pp. 218-
-315, and "Global Challenges for New Drug Discovery Against Tropical Parasitic Diseases",
pp. 316--357. 4 (3): 278–286. doi:10.1016/j.ijpddr.2014.09.001 (https://doi.org/10.1016%2Fj.i
jpddr.2014.09.001). PMC 4266796 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC426679
6). PMID 25516838 (https://pubmed.ncbi.nlm.nih.gov/25516838).
8. Harvey AL (October 2008). "Natural products in drug discovery". Drug Discovery Today. 13
(19–20): 894–901. doi:10.1016/j.drudis.2008.07.004 (https://doi.org/10.1016%2Fj.drudis.200
8.07.004). PMID 18691670 (https://pubmed.ncbi.nlm.nih.gov/18691670).
9. Cragg GM, Newman DJ (June 2013). "Natural products: a continuing source of novel drug
leads" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672862). Biochimica et Biophysica
Acta (BBA) - General Subjects. 1830 (6): 3670–3695. doi:10.1016/j.bbagen.2013.02.008 (htt
ps://doi.org/10.1016%2Fj.bbagen.2013.02.008). PMC 3672862 (https://www.ncbi.nlm.nih.go
v/pmc/articles/PMC3672862). PMID 23428572 (https://pubmed.ncbi.nlm.nih.gov/23428572).
10. Carey JS, Laffan D, Thomson C, Williams MT (June 2006). "Analysis of the reactions used
for the preparation of drug candidate molecules". Organic & Biomolecular Chemistry. 4 (12):
2337–2347. doi:10.1039/B602413K (https://doi.org/10.1039%2FB602413K).
PMID 16763676 (https://pubmed.ncbi.nlm.nih.gov/16763676). S2CID 20800243 (https://api.s
emanticscholar.org/CorpusID:20800243).
11. Dalton LW (2003). "Careers for 2003 and Beyond: Medicinal Chemistry" (http://pubs.acs.org/
cen/employment/8125/8125medicinal.html). Chemical & Engineering News. 81 (25): 53–54,
56. doi:10.1021/cen-v081n025.p053 (https://doi.org/10.1021%2Fcen-v081n025.p053).

External links
Biochemistry and Molecular Biology (https://curlie.org//Science/Biology/Biochemistry_and_Molecular_Bi
ology/) at Curlie

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