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Medicinal chemistry
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<h2 id="in-the-path-of-drug-discovery">In the path of drug discovery</h2> <h3>Discovery</h3> <p>Discovery is the identification of novel active chemical compounds, often called "hits", which are typically found by assay of compounds for a desired <a href="/facts/Biological_activity/jJ14jyvc">biological activity</a>.<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a> Initial hits can come from repurposing existing agents toward a new pathologic processes,<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> and from observations of biologic effects of new or existing <a href="/facts/Natural_products/J4RsVhmP">natural products</a> from bacteria, fungi,<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> plants,<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> etc. In addition, hits also routinely originate from structural observations of small molecule "fragments" bound to therapeutic targets <a href="/facts/Enzyme/DSI1Fh7y">(enzymes</a>, receptors, etc.), where the fragments serve as starting points to develop more chemically complex forms by synthesis. Finally, hits also regularly originate from <i>en-masse</i> testing of chemical compounds against biological targets using biochemical or <a href="/facts/Chemoproteomics/rGTpmJaR">chemoproteomics</a> 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 <a href="/facts/Combinatorial_chemistry/WW2SSJnq">combinatorial chemistry</a>. 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. </p> <h3>Hit to lead and lead optimization</h3> <p class="note">See also: <a href="/facts/Lead_optimization/HM0Azefd">Lead optimization</a></p> <p>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 the remaining hit series concerning 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 (<a href="/facts/Pharmacophore/H6GYHHEq">pharmacophores</a>) of the candidate compounds, and so their affinities for their targets, as well as improving the physicochemical properties of the molecule that underlie necessary <a href="/facts/Pharmacokinetic/x4CUUnle">pharmacokinetic</a>/<a href="/facts/Pharmacodynamic/zdvfFshl">pharmacodynamic</a> (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. </p> <h3>Process chemistry and development</h3> <p>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 <a href="/facts/Clinical_trials/q8LMr832">clinical trials</a>. This involves the optimization of the <a href="/facts/Chemical_synthesis/3KXsVVwC">synthetic</a> route for bulk industrial production, and discovery of the most suitable drug <a href="/facts/Formulation/GyvpXvsL">formulation</a>. 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 <a href="/facts/Good_manufacturing_practice/s4sETf1y">GMP</a> requirements for material sourcing, handling, and chemistry. </p> <h3>Synthetic analysis</h3> <p>The synthetic methodology employed in medicinal chemistry is subject to constraints that do not apply to traditional <a href="/facts/Organic_synthesis/aprl6Iq7">organic synthesis</a>. Owing to the prospect of scaling the preparation, safety is of paramount importance. The potential toxicity of reagents affects methodology.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a><a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> </p> <h3>Structural analysis</h3> <p>The structures of pharmaceuticals are assessed in many ways, in part as a means to predict efficacy, stability, and accessibility. <a href="/facts/Lipinski%27s_rule_of_five/VcJgQSj8">Lipinski's rule of five</a> 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. </p><p>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).<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> </p> <h2 id="training">Training</h2> <p>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.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> 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.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> 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. </p><p>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,<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> and the preponderance of positions are in research, where the net is necessarily cast widest, and most broad synthetic activity occurs. </p><p>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.). </p><p>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.) </p> <h2 id="see-also">See also</h2> <ul> <li>Chemistry portal</li><li>Science portal</li></ul> <ul><li><a href="/facts/Bioisostere/M7R0LGfp">Bioisostere</a></li> <li><a href="/facts/Biological_machine/5VvXFnoq">Biological machines</a></li> <li><a href="/facts/Chemoproteomics/rGTpmJaR">Chemoproteomics</a></li> <li><a href="/facts/Drug_design/XAU0Ke3d">Drug design</a></li> <li><a href="/facts/Pharmacognosy/X3rrkkA9">Pharmacognosy</a></li> <li><a href="/facts/Pharmacokinetics/x4CUUnle">Pharmacokinetics</a></li> <li><a href="/facts/Pharmacology/4Rx8s7Ie">Pharmacology</a></li> <li><a href="/facts/Pharmacophore/H6GYHHEq">Pharmacophore</a></li> <li><a href="/facts/Xenobiotic_metabolism/I5nQ28Ma">Xenobiotic metabolism</a></li></ul> Look up <i>medicinal chemistry</i> in Wiktionary, the free dictionary. <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Davis A, Ward SE, eds. (2015). The Handbook of Medicinal Chemistry. Royal Society of Chemistry. doi:10.1039/9781782621836. ISBN 978-1-78262-419-6. <a href="978-1-78262-419-6" target="_blank">978-1-78262-419-6</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Barret R (2018). Medicinal Chemistry: Fundamentals. London: Elsevier. ISBN 978-1-78548-288-5. <a href="978-1-78548-288-5" target="_blank">978-1-78548-288-5</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Hanif M, Yang X, Tinoco AD, Plażuk D (2020-05-28). "Editorial: New Strategies in Design and Synthesis of Inorganic Pharmaceuticals". Frontiers in Chemistry. 8: 453. Bibcode:2020FrCh....8..453H. doi:10.3389/fchem.2020.00453. PMC 7270431. PMID 32548093. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270431" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270431</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>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". Chemical Science. 11 (48): 12888–12917. doi:10.1039/D0SC04082G. PMC 8163330. PMID 34123239. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163330" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163330</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>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. PMID 21504168. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Hughes JP, Rees S, Kalindjian SB, Philpott KL (March 2011). "Principles of early drug discovery". British Journal of Pharmacology. 162 (6): 1239–1249. doi:10.1111/j.1476-5381.2010.01127.x. PMC 3058157. PMID 21091654. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058157" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058157</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>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". 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. PMC 4266796. PMID 25516838. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266796" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266796</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>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. PMID 18691670. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>Cragg GM, Newman DJ (June 2013). "Natural products: a continuing source of novel drug leads". Biochimica et Biophysica Acta (BBA) - General Subjects. 1830 (6): 3670–3695. doi:10.1016/j.bbagen.2013.02.008. PMC 3672862. PMID 23428572. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672862" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672862</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>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. PMID 21504168. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> <li id="fn:11"><p>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. PMID 16763676. S2CID 20800243. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></p></li> <li id="fn:12"><p>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. PMID 21504168. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></p></li> <li id="fn:13"><p>Foye, W. O., Lemke, T. L., & Williams, D. A. Principles of Medicinal Chemistry 7th edition, (2013) Lippincott Williams & Wilkins 1,168 pages ISBN: 978-1451111536 <a href="#fnref:13" class="footnote-back-ref">↩</a></p></li> <li id="fn:14"><p>Silverman, R. B., & Wipf, P. Medicinal Chemistry: A Molecular and Biochemical Approach 2nd edition, (2005) Oxford University Press 464 pages ISBN: 978-0195166070 <a href="#fnref:14" class="footnote-back-ref">↩</a></p></li> <li id="fn:15"><p>Dalton LW (2003). "Careers for 2003 and Beyond: Medicinal Chemistry". Chemical & Engineering News. 81 (25): 53–54, 56. doi:10.1021/cen-v081n025.p053. <a href="http://pubs.acs.org/cen/employment/8125/8125medicinal.html" target="_blank">http://pubs.acs.org/cen/employment/8125/8125medicinal.html</a> <a href="#fnref:15" class="footnote-back-ref">↩</a></p></li> </ol>