Allosteric modulation of GPCRs: From structural insights to in silico drug discovery

G protein-coupled receptors (GPCRs) play critical roles in human physiology and are one of the prime targets for marketed drugs. While traditional drug discovery programs have focused on the development of ligands targeting the binding site of endogenous ligands (orthosteric site), allosteric modulators offer new avenues for the regulation of GPCR function with potential therapeutic benefits. Recent advances in the structure determina-tion of GPCRs bound to different types of allosteric modulators have led to the identification of multiple allosteric sites and significantly enhanced our understanding of how allosteric ligands interact with receptors. These struc-tural insights, together with the plethora of GPCR structures available today, will facilitate structure-based dis-covery and development of allosteric modulators as novel therapeutic candidates. In this review, we provide a systematic analysis of the currently available GPCR structures in complex with small-molecule allosteric ligands in terms of the location of allosteric pockets, receptor-ligand interactions, and the chemical features of the allo-steric modulators. In addition, we summarize current strategies for the identification of allosteric sites as well as ligand-based and structure-based drug discovery and design.(c) 2022 Elsevier Inc. All rights reserved.

Automated summary

G protein-coupled receptors (GPCRs) are important targets for drug development, and allosteric modulators offer new avenues for regulating their function. Recent advances in determining the structures of GPCRs bound to allosteric modulators have enhanced our understanding of their interactions and will facilitate the discovery of novel therapeutic candidates.