Department of Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 8, Marburg 35032, Germany.
Department of Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 8, Marburg 35032, Germany.
Pharmacol Ther. 2022 Sep;237:108242. doi: 10.1016/j.pharmthera.2022.108242. Epub 2022 Jul 18.
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（GPCRs）在人体生理学中发挥着关键作用，是上市药物的主要靶点之一。虽然传统的药物发现计划侧重于开发针对内源性配体结合位点（变构位点）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。最近在与不同类型变构调节剂结合的 GPCR 结构测定方面的进展，导致了多个变构位点的鉴定，并大大提高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，以及当今大量可用的 GPCR 结构，将促进基于结构的发现和开发变构调节剂作为新型治疗候选物。在这篇综述中，我们从变构口袋的位置、受体-配体相互作用以及变构调节剂的化学特征等方面，对目前与小分子变构配体结合的 GPCR 结构进行了系统分析。此外，我们总结了目前鉴定变构位点的策略，以及基于配体和基于结构的药物发现和设计。
