Lead compound
A lead compound (/ˈliːd/, i.e., a "leading" compound; not to be confused with various compounds of the element lead) in drug discovery is a chemical compound that has pharmacological or biological activity likely to be therapeutically useful, but may nevertheless have suboptimal structure that requires modification to fit better to the target; lead drugs offer the prospect of being followed by "back-up" compounds. The chemical structure serves as a starting point for chemical modifications in order to improve potency, selectivity, or pharmacokinetic parameters. Furthermore, newly-invented pharmacologically active moieties may have poor druglikeness and may require chemical modification to become "drug-like" enough to be tested biologically or clinically.[1]
Lead compounds are sometimes called developmental candidates.[1] This is because the discovery and selection of lead compounds occurs prior to preclinical and clinical development of the candidate.
Discovering lead compounds
[edit]Discovery of a drugable target
[edit]Before lead compounds can be discovered, a suitable target for rational drug design must be selected on the basis of biological plausibility, or identified through screening potential lead compounds against multiple targets.[1] Drug libraries are often tested by high-throughput screenings (active compounds are designated as "hits") which can screen compounds for their ability to inhibit (antagonize) or stimulate (agonize) a target of interest as well as determine selectivity for these targets.[1]
Development of a lead compound
[edit]A lead compound may arise from a variety of different sources. Lead compounds are found by characterizing natural products, employing combinatorial chemistry, or by molecular modeling as in rational drug design.[2] Chemicals identified as "hits" through high-throughput screening may also become lead compounds.[1]
Once a lead compound is selected, it must undergo lead optimization, which involves making the compound more "drug-like."[1] This is where Lipinski's rule of five comes into play, sometimes also referred to as the "Pfizer rule" or simply as the "rule of five".[3] Other factors, such as the ease of scaling up the manufacturing of the chemical, must be taken into consideration as well.[3]
See also
[edit]- Drug development – Process of bringing a new pharmaceutical drug to the market
- Drug design – Invention of new medications based on knowledge of a biological target
- Rational drug design – Invention of new medications based on knowledge of a biological target
- Drug discovery hit to lead – Stage of drug discovery
- Lead optimization – Stage of drug discovery
References
[edit]- ^ a b c d e f Hughes JP, Rees S, Kalindjian SB, Philpott KL (March 2011). "Principles of early drug discovery". British Journal of Pharmacology. 162 (6). Wiley-Blackwell: 1239–1249. doi:10.1111/j.1476-5381.2010.01127.x. PMC 3058157. PMID 21091654.
- ^ Boa AN. "Introduction To Drug Discovery" (PDF). Department of Chemistry, University of Hull. Archived from the original (PDF) on 2017-05-17. Retrieved 2013-11-13.
- ^ a b Schneider G (2013). "Prediction of Drug-Like Properties". Madame Curie Bioscience Database. Austin, TX: Landes Bioscience. Retrieved 20 November 2017 – via US National Library of Medicine.
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