Computational investigation of the antagonism effect towards GluN2B-Containing NMDA receptor: Combined ligand-based and target-based approach

J Mol Graph Model. 2019 Jan:86:95-105. doi: 10.1016/j.jmgm.2018.10.009. Epub 2018 Oct 10.

Abstract

The interaction of GluN2B-Containing NMDA Receptor with 18 antagonists were investigated by a combined ligand-based and target-based approach. First, two distinct pharmacophore models were generated for antagonists which cluster in two groups with Catalyst (HipHop module). The pharmacophore of "ifenprodil group" antagonists includes three hydrophobic groups, one H-bond donor and one H-bond acceptor, the pharmacophore of "EVT101 group" antagonists involves one aromatic ring, two hydrophobic groups and one H-bond acceptor. Docking results and pharmacophore model confrontation allow the pharmacodynamic characteristics to be weighted and structural information integrated. Which results in the proposal of two interaction models inside the GluN2B binding cavity for two groups of antagonists. The interaction model of "ifenprodil group" antagonists consists of one hydrophobic group, one H-bond donor, one H-bond acceptor and an aromatic ring, while on the other hand, the interaction model of "EVT101 group" antagonists includes three hydrophobic groups and an aromatic ring.

Keywords: Molecular simulations; NMDA receptor; Neurodegenerative disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalytic Domain
  • Drug Design*
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Ligands*
  • Models, Molecular*
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / chemistry*

Substances

  • Ligands
  • NR2B NMDA receptor
  • Receptors, N-Methyl-D-Aspartate