Journal
DRUG DISCOVERY TODAY
Volume 24, Issue 9, Pages 1806-1820Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.drudis.2019.06.007
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Funding
- National Institute of Mental Health's Psychoactive Drug Screening Program [HHSN-271-201300017-C]
- European H2020 ESCAPE-NET Project [733381]
- RETOS project from the Spanish Ministerio de Ciencia, Innovacion y Universidades [SAF2017-83614-R]
- National Institutes of Health Common Fund program [U24 CA224370, U24 TR002278, U01 CA239108]
- H2020 Societal Challenges Programme [733381] Funding Source: H2020 Societal Challenges Programme
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We have limited understanding of the variation in in vitro affinities of drugs for their targets. An analysis of a highly curated set of 815 interactions between 566 drugs and 129 primary targets reveals that 71% of drug-target affinities have values above that of the corresponding endogenous ligand, 96% of them fitting within a range of two orders of magnitude. Our findings suggest that the evolutionary optimised affinity of endogenous ligands for their native proteins can serve as a baseline for the primary pharmacology of drugs. We show that the degree of off-target selectivity and safety risks of drugs derived from their secondary pharmacology depend very much on that baseline. Thus, we propose a new approach for estimating safety margins.
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