{{Short description|Concept in drug discovery}} {{About|the pharmaceutical concept|compounds containing the element lead|Lead compounds|use of lead in structures|Lead#Applications{{!}}Lead § Applications}} {{cs1 config|name-list-style=vanc}} A '''lead compound''' ({{IPAc-en|ˈ|l|iː|d}}, 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 {{shy|pharma|co|logical}} or biological activity likely to be therapeutically useful, but may {{shy|never|the|less}} have suboptimal structure that requires modification to fit better to the target; lead drugs offer the prospect of being followed by {{nowr|"back-up"}} compounds. The chemical structure serves as a starting point for chemical modifications in order to improve potency, selectivity, or {{shy|pharma|co|kinetic}} parameters. Furthermore, newly-invented {{shy|pharma|co|logically}} active moieties may have poor druglikeness and may require chemical modification to become {{nowr|"drug-like"}} enough to be tested biologically or clinically.<ref name="Early Drug Discovery">{{cite journal|last1=Hughes|first1=JP|last2=Rees|first2=S|last3=Kalindjian|first3=SB|last4=Philpott|first4=KL|title=Principles of early drug discovery|journal=British Journal of Pharmacology|publisher=Wiley-Blackwell|date=March 2011|volume=162|issue=6|pages=1239–1249|doi=10.1111/j.1476-5381.2010.01127.x|pmc=3058157|pmid=21091654}}</ref>
Lead compounds are sometimes called ''developmental candidates''.<ref name="Early Drug Discovery" /> This is because the discovery and selection of lead compounds occurs prior to preclinical and clinical development of the candidate.
==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.<ref name="Early Drug Discovery" /> Drug libraries are often tested by {{nowr|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.<ref name="Early Drug Discovery" />
===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.<ref>{{Cite web |url=http://www.hull.ac.uk/php/chsanb/DrugDisc/IntroDrugDiscovery%202007.pdf |last=Boa |first=AN |publisher=Department of Chemistry, University of Hull |title=Introduction To Drug Discovery |access-date=2013-11-13 |archive-date=2017-05-17 |archive-url=https://web.archive.org/web/20170517015134/http://www.hull.ac.uk/php/chsanb/DrugDisc/IntroDrugDiscovery%202007.pdf |url-status=dead }}</ref> Chemicals identified as "hits" through {{nowr|high-throughput}} screening may also become lead compounds.<ref name="Early Drug Discovery" />
Once a lead compound is selected, it must undergo lead optimization, which involves making the compound more "drug-like."<ref name="Early Drug Discovery" /> This is where Lipinski's rule{{nbsp}}of five comes into play, sometimes also referred to as the "Pfizer{{nbsp}}rule" or simply as the "rule{{nbsp}}of five".<ref name="Drug-likeness">{{cite encyclopedia|last1=Schneider|first1=Gisbert|title=Prediction of Drug-Like Properties|url=https://www.ncbi.nlm.nih.gov/books/NBK6404/|encyclopedia=Madame Curie Bioscience Database|publisher=Landes Bioscience|publication-place=Austin, TX|via=US National Library of Medicine|accessdate=20 November 2017|language=en|date=2013}}</ref> Other factors, such as the ease of scaling{{nbsp}}up the manufacturing of the chemical, must be taken into consideration as well.<ref name="Drug-likeness" />
==See also== * {{anl|Drug development}} * {{anl|Drug design}} ** {{anl|Rational drug design}} * {{anl|Drug discovery hit to lead}} ** {{anl|Lead optimization}}
==References== {{reflist}}
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Category:Drug discovery Category:Medicinal chemistry