The human endogenous metabolome as a pharmacology baseline for drug discovery

TY - JOUR

T1 - The human endogenous metabolome as a pharmacology baseline for drug discovery

AU - Bofill, Andreu

AU - Jalencas, Xavier

AU - Oprea, Tudor I.

AU - Mestres, Jordi

PY - 2019/9

Y1 - 2019/9

N2 - 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. Two-thirds of drugs have more-potent in vitro affinities for their primary targets than those of the corresponding endogenous ligands, which define a baseline to estimate off-target safety margins.

AB - 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. Two-thirds of drugs have more-potent in vitro affinities for their primary targets than those of the corresponding endogenous ligands, which define a baseline to estimate off-target safety margins.

U2 - 10.1016/j.drudis.2019.06.007

DO - 10.1016/j.drudis.2019.06.007

M3 - Review

C2 - 31226432

SN - 1359-6446

VL - 24

SP - 1806

EP - 1820

JO - Drug Discovery Today: BIOSILICO

JF - Drug Discovery Today: BIOSILICO

IS - 9-12

ER -