Subtype-selective mechanisms of negative allosteric modulators binding to group I metabotropic glutamate receptors

Ting-ting Fu1,2, Gao Tu1,2, Meng Ping1, Guo-xun Zheng1,2, Feng-yuan Yang1,2, Jing-yi Yang1,2, Yang Zhang1,2, Xiao-jun Yao3, Wei-wei Xue1, Feng Zhu1,2
1 School of Pharmaceutical Sciences, Collaborative Innovation Center for Brain Science and Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Chongqing 401331, China
2 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
3 State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, China
Correspondence to: Wei-wei Xue:, Feng Zhu:,
DOI: 10.1038/s41401-020-00541-z
Received: 14 July 2020
Accepted: 15 September 2020
Advance online: 29 October 2020


Group I metabotropic glutamate receptors (mGlu1 and mGlu5) are promising targets for multiple psychiatric and neurodegenerative disorders. Understanding the subtype selectivity of mGlu1 and mGlu5 allosteric sites is essential for the rational design of novel modulators with single- or dual-target mechanism of action. In this study, starting from the deposited mGlu1 and mGlu5 crystal structures, we utilized computational modeling approaches integrating docking, molecular dynamics simulation, and efficient post- trajectory analysis to reveal the subtype-selective mechanism of mGlu1 and mGlu5 to 10 diverse drug scaffolds representing known negative allosteric modulators (NAMs) in the literature. The results of modeling identified six pairs of non-conserved residues and four pairs of conserved ones as critical features to distinguish the selective NAMs binding to the corresponding receptors. In addition, nine pairs of residues are beneficial to the development of novel dual-target NAMs of group I metabotropic glutamate receptors. Furthermore, the binding modes of a reported dual-target NAM (VU0467558) in mGlu1 and mGlu5 were predicted to verify the identified residues that play key roles in the receptor selectivity and the dual-target binding. The results of this study can guide rational structure-based design of novel NAMs, and the approach can be generally applicable to characterize the features of selectivity for other G-protein-coupled receptors.
Keywords: metabotropic glutamate receptors; negative allosteric modulators; drug selectivity; computational modeling; psychiatric and neurodegenerative disorders

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