G protein-coupled receptors(GPCRs):advances in structures,mechanisms,and drug discovery  

作　　者：Mingyang Zhang Ting Chen Xun Lu Xiaobing Lan Ziqiang Chen Shaoyong Lu 

机构地区：[1]Key Laboratory of Protection,Development and Utilization of Medicinal Resources in Liupanshan Area,Ministry of Education,Peptide&Protein Drug Research Center,School of Pharmacy,Ningxia Medical University,Yinchuan 750004,China [2]Medicinal Chemistry and Bioinformatics Center,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China [3]Department of Cardiology,Changzheng Hospital,Affiliated to Naval Medical University,Shanghai 200003,China [4]Department of Orthopedics,Changhai Hospital,Affiliated to Naval Medical University,Shanghai 200433,China

出　　处：《Signal Transduction and Targeted Therapy》2024年第5期1938-1980,共43页信号转导与靶向治疗（英文）

基　　金：This study was supported by grants from the National Key R&D Program of the Ministry of Science and Technology(No.2023YFC3404700);the National Natural Science Foundation of China(No.22077082);the Shanghai Frontiers Science Center of Cellular Homeostasis and the Human Diseases,and the Innovative Research Team of High-Level Local Universities in Shanghai.

摘　　要：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.

关 键 词：STERIC DESIGNING MECHANISMS 

分 类 号：O62[理学—有机化学]