Small Molecule Allosteric Modulators of G-Protein-Coupled Receptors: Drug-Target Interactions
Small Molecule Allosteric Modulators of G-Protein-Coupled Receptors: Drug-Target Interactions
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DOI：
10.1021/acs.jmedchem.7b01844
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发表时间：
2019-01-10
影响因子：
7.3
通讯作者：
Zhang, Jian
中科院分区：
文献类型：
--
作者：
Lu, Shaoyong;Zhang, Jian
G蛋白偶联受体（GPCR）是最大的一类信号受体，最常被治疗药物靶向。与传统的正构配体相比，在变构位点与GPCR结合的变构调节剂提供了差异选择性和改善的安全性的潜力。最近在GPCR结构生物学方面的突破已经使得来自A、B、C和F类的GPCR与小分子变构调节剂复合的结构可用。在变构位点的详细受体-调节剂相互作用的知识对于基于结构的新型治疗剂的GPCR药物设计是有用的。本文综述了GPCR与小分子变构调节剂之间的结构复合物的研究现状，特别是在变构位点的关键受体调节剂相互作用。然后，在四个GPCR亚家族的变构位点的结构多样性进行了比较。该研究有望为设计具有更好治疗作用的GPCR变构药物做出贡献。
G-protein-coupled receptors (GPCRs) are the largest class of signaling receptors that are most frequently targeted by therapeutic drugs. Allosteric modulators bound to GPCRs at allosteric sites provide the potential for differential selectivity and improved safety compared with traditional orthosteric ligands. The recent breakthroughs in GPCR structural biology have made structures of GPCRs from classes A, B, C, and F complexed with small-molecule allosteric modulators available. Knowledge of the detailed receptor-modulator interactions at the allosteric sites is useful for structure-based GPCR drug design of novel therapeutics. This Perspective comprehensively summarizes the current status of structural complexes between GPCRs and their small-molecule allosteric modulators, particularly the key receptor modulator interactions at the allosteric sites. Then, the structural diversity of allosteric sites across four GPCR subfamilies is compared. This study is expected to contribute to the design of GPCR allosteric drugs with an improved therapeutic action.