G protein-coupled receptors (GPCRs), the largest family of human membrane proteins and an important class of drug targets, play a role in maintaining numerous physiological processes. Agonist or antagonist, orthosteric effects or allosteric effects, and biased signaling or balanced signaling, characterize the complexity of GPCR dynamic features. In this study, we first review the structural advancements, activation mechanisms, and functional diversity of GPCRs. We then focus on GPCR drug discovery by revealing the detailed drug-target interactions and the underlying mechanisms of orthosteric drugs approved by the US Food and Drug Administration in the past five years. Particularly, an up-to-date analysis is performed on available GPCR structures complexed with synthetic small-molecule allosteric modulators to elucidate key receptor-ligand interactions and allosteric mechanisms. Finally, we highlight how the widespread GPCR-druggable allosteric sites can guide structure- or mechanism-based drug design and propose prospects of designing bitopic ligands for the future therapeutic potential of targeting this receptor family.

G蛋白偶联受体（GPCR）是最大的人类膜蛋白家族和一类重要的药物靶标，在维持许多生理过程中发挥着作用。激动剂或拮抗剂、正构效应或变构效应、偏向信号传导或平衡信号传导，表征了 GPCR 动态特征的复杂性。在本研究中，我们首先回顾了 GPCR 的结构进展、激活机制和功能多样性。然后，我们通过揭示过去五年美国食品和药物管理局批准的正构药物的详细药物-靶点相互作用和潜在机制，重点关注 GPCR 药物发现。特别是，对与合成小分子变构调节剂复合的可用 GPCR 结构进行了最新分析，以阐明关键的受体-配体相互作用和变构机制。最后，我们强调了广泛的 GPCR 成药变构位点如何指导基于结构或机制的药物设计，并提出了设计双位配体的前景，以实现针对该受体家族的未来治疗潜力。