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Drug Discov Today. 2019 Jun 19. pii: S1359-6446(19)30104-7. doi: 10.1016/j.drudis.2019.06.007. [Epub ahead of print]

The human endogenous metabolome as a pharmacology baseline for drug discovery.

Author information

1
Research Group on Systems Pharmacology, Research Program on Biomedical Informatics (GRIB), IMIM Hospital del Mar Medical Research Institute and University Pompeu Fabra, 08003 Barcelona, Catalonia, Spain.
2
Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA; UNM Comprehensive Cancer Center, Albuquerque, NM, USA; Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
3
Research Group on Systems Pharmacology, Research Program on Biomedical Informatics (GRIB), IMIM Hospital del Mar Medical Research Institute and University Pompeu Fabra, 08003 Barcelona, Catalonia, Spain. Electronic address: jmestres@imim.cat.

Abstract

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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