Recent Progress in Structure-Based Evaluation of Compound Promiscuity

Abstract

In chemistry and drug discovery, compound promiscuity is a controversial issue and often viewed differently. On the one hand, promiscuity has a clear-cut negative connotation, as promiscuous behavior of small molecules is often associated with nonspecific binding or assay artifacts. On the other hand, it is also well-established that compounds frequently interact with multiple targets including distantly related or unrelated proteins. In drug discovery, multitarget activity of small molecules receives increasing attention because it is therapeutically relevant, giving rise to desired or undesired pharmacological effects. Exploration of compound promiscuity is far from being simple because true and artificial activities are often difficult to discern. In light of these complications, X-ray structures of ligand-target complexes provide a wealth of information about molecular promiscuity, which is just beginning to be recognized and explored. Systematic analysis of structurally confirmed binding events involving artifact-prone compounds or multitarget ligands eliminates some of the uncertainties associated with promiscuity analysis and puts it on a new level, enabling the study of promiscuity-conferring interactions at the molecular level of detail. Herein, we discuss recent progress made in structure-based promiscuity analysis and put key findings into scientific context. ©