Lead compound

Short description: Concept in drug discovery

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.

## Contents

* 1 Discovering lead compounds
* 1.1 Discovery of a drugable target
* 1.2 Development of a lead compound
* 2 See also
* 3 References

## Discovering lead compounds

### Discovery of a drugable target

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

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

* Drug development
* Drug design - Invention of new medications based on knowledge of a biological target
* Rational drug design
* Drug discovery hit to lead
* Lead optimization

## References

1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Hughes, JP; Rees, S; Kalindjian, SB; Philpott, KL (March 2011). "Principles of early drug discovery". British Journal of Pharmacology (Wiley-Blackwell) 162 (6): 1239–1249. doi:10.1111/j.1476-5381.2010.01127.x. PMID 21091654.
2. ↑ Boa, AN. "Introduction To Drug Discovery". Department of Chemistry, University of Hull. http://www.hull.ac.uk/php/chsanb/DrugDisc/IntroDrugDiscovery 2007.pdf.
3. ↑ 3.0 3.1 Schneider, Gisbert (2013). "Prediction of Drug-Like Properties" (in en). Madame Curie Bioscience Database. Austin, TX: Landes Bioscience. https://www.ncbi.nlm.nih.gov/books/NBK6404/. Retrieved 20 November 2017.

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