The human endogenous metabolome as a pharmacology baseline for drug discovery

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.