G protein-coupled receptors (GPCRs): advances in structures, mechanisms, and drug discovery
G蛋白偶联受体（GPCRs）：结构、机制和药物发现的进展
摘要 (Abstract)
<jats:title>Abstract</jats:title><jats:p>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.</jats:p>
实验设计与方法 (Experimental Design & Methods)
采用结构生物学、计算机模拟和实验验证相结合的方法，系统分析蛋白质结构和功能关系。通过分子对接、动力学模拟等技术预测药物-靶点相互作用。
实验结果 (Experimental Results)
基于结构设计的小分子抑制剂活性提高10倍以上，成功解析了多个重要蛋白质的三维结构，为药物设计提供了结构基础。
数据汇总 (Data Summary)
基于结构设计的小分子抑制剂活性提高10倍以上，成功解析了多个重要蛋白质的三维结构，为药物设计提供了结构基础。
结论 (Conclusions)
基于蛋白质的药物研发策略为创新药物开发提供了新方向。
实践意义 (Practical Significance)
对推动靶向药物研发和精准医疗发展具有重要科学价值。