Structure-Based Optimization Strategies for G Protein-Coupled Receptor (GPCR) Allosteric Modulators: A Case Study from Analyses of New Metabotropic Glutamate Receptor 5 (mGlu5) X-ray Structures,Journal of Medicinal Chemistry

当前位置： X-MOL 学术 › J. Med. Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Structure-Based Optimization Strategies for G Protein-Coupled Receptor (GPCR) Allosteric Modulators: A Case Study from Analyses of New Metabotropic Glutamate Receptor 5 (mGlu5) X-ray Structures
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-02-18 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01722
John A. Christopher ₁ , Zoltán Orgován ₂ , Miles Congreve ₁ , Andrew S. Doré ₁ , James C. Errey ₁ , Fiona H. Marshall ₁ , Jonathan S. Mason ₁ , Krzysztof Okrasa ₁ , Prakash Rucktooa ₁ , Maria J. Serrano-Vega ₁ , György G. Ferenczy ₂ , György M. Keserű ₂

Affiliation

Two interesting new X-ray structures of negative allosteric modulator (NAM) ligands for the mGlu₅ receptor, M-MPEP (3) and fenobam (4), are reported. The new structures show how the binding of the ligands induces different receptor water channel conformations to previously published structures. The structure of fenobam, where a urea replaces the acetylenic linker in M-MPEP and mavoglurant, reveals a binding mode where the ligand is rotated by 180° compared to a previously proposed docking model. The need for multiple ligand structures for accurate GPCR structure-based drug design is demonstrated by the different growing vectors identified for the head groups of M-MPEP and mavoglurant and by the unexpected water-mediated receptor interactions of a new chemotype represented by fenobam. The implications of the new structures for ligand design are discussed, with extensive analysis of the energetics of the water networks of both pseudoapo and bound structures providing a new design strategy for allosteric modulators.

中文翻译：

G蛋白偶联受体（GPCR）变构调节剂的基于结构的优化策略：从新的代谢型谷氨酸受体5（mGlu ₅）X射线结构分析的案例研究

负变构调节剂（NAM）配体的两个有趣的新X射线结构，用于mGlu ₅受体，M-MPEP（3）和芬诺班（4），均已报告。新结构显示了配体的结合如何诱导与先前发表的结构不同的受体水通道构象。非诺贝特的结构（其中尿素取代了M-MPEP和mavglurant中的炔属接头）揭示了一种结合模式，与先前提出的对接模型相比，配体旋转了180°。为M-MPEP和mavgluant头基确定的不同生长载体以及以非诺贝姆为代表的新化学型的意想不到的水介导的受体相互作用证明了对多种配体结构进行精确GPCR结构为基础的药物设计的需求。讨论了新结构对配体设计的影响，

更新日期：2018-02-18

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11