Exploring the Binding Mechanism of Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators in Clinical Trials by Molecular Dynamics Simulations

ACS Chem Neurosci. 2018 Jun 20;9(6):1492-1502. doi: 10.1021/acschemneuro.8b00059. Epub 2018 Mar 16.


Metabotropic glutamate receptor 5 (mGlu5) plays a key role in synaptic information storage and memory, which is a well-known target for a variety of psychiatric and neurodegenerative disorders. In recent years, the increasing efforts have been focused on the design of allosteric modulators, and the negative allosteric modulators (NAMs) are the front-runners. Recently, the architecture of the transmembrane (TM) domain of mGlu5 receptor has been determined by crystallographic experiment. However, it has been not well understood how the pharmacophores of NAMs accommodated into the allosteric binding site. In this study, molecular dynamics (MD) simulations were performed on mGlu5 receptor bound with NAMs in preclinical or clinical development to shed light on this issue. In order to identify the key residues, the binding free energies as well as per-residue contributions for NAMs binding to mGlu5 receptor were calculated. Subsequently, the in silico site-directed mutagenesis of the key residues was performed to verify the accuracy of simulation models. As a result, the shared common features of the studied 5 clinically important NAMs (mavoglurant, dipraglurant, basimglurant, STX107, and fenobam) interacting with 11 residues in allosteric site were obtained. This comprehensive study presented a better understanding of mGlu5 receptor NAMs binding mechanism, which would be further used as a useful framework to assess and discover novel lead scaffolds for NAMs.

Keywords: Metabotropic glutamate receptor 5; drug design; molecular dynamics; negative allosteric modulators; psychiatric and neurodegenerative disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects
  • Humans
  • Imidazoles / pharmacology*
  • Molecular Docking Simulation / methods
  • Molecular Dynamics Simulation*
  • Protein Binding / drug effects*
  • Pyridines / pharmacology*
  • Receptor, Metabotropic Glutamate 5 / drug effects
  • Receptor, Metabotropic Glutamate 5 / metabolism*


  • 2-chloro-4-(1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl)pyridine
  • Imidazoles
  • Pyridines
  • Receptor, Metabotropic Glutamate 5
  • 6-fluoro-2-(4-(pyridin-2-yl)but-3-yn-1-yl)imidazo(1,2-a)pyridine