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 determination 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 structural insights, together with the plethora of GPCR structures available today, will facilitate structure-based discovery 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 allosteric 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.

G 蛋白偶联受体 (GPCR) 在人体生理学中发挥着关键作用，是上市药物的主要靶标之一。虽然传统的药物发现计划专注于开发靶向内源性配体结合位点（正构位点）的配体，但变构调节剂为调节 GPCR 功能提供了新的途径，具有潜在的治疗益处。与不同类型的变构调节剂结合的 GPCR 结构测定的最新进展导致了多个变构位点的识别，并显着增强了我们对变构配体如何与受体相互作用的理解。这些结构见解，连同当今可用的大量 GPCR 结构，将促进基于结构的变构调节剂作为新型治疗候选物的发现和开发。在这篇综述中，我们就变构袋的位置、受体-配体相互作用和变构调节剂的化学特征对目前可用的与小分子变构配体复合的 GPCR 结构进行了系统分析。此外，我们总结了当前用于识别变构位点以及基于配体和基于结构的药物发现和设计的策略。