Molecular modeling of noncompetitive antagonists of the NMDA receptor: proposal of a pharmacophore and a description of the interaction mode

J Mol Model. 2002 Feb;8(2):65-72. doi: 10.1007/s00894-001-0067-4.

Abstract

Since the three-dimensional structure of the NMDA receptor has not been determined experimentally, indirect computer-assisted molecular modeling techniques appear to be of great usefulness in the characterization of the common pharmacophore of all NMDA receptor noncompetitive antagonists, despite their structural differences. Indeed, the conformational analysis of three different chemical families (MK801, PCP, dexoxadrol and their analogues), has allowed us to visualize the different conformations and configurations of each molecule. Superimposition with configurations 1 and 2 of the MK801 molecule has allowed us to propose active conformations and thereafter a geometrical characterization of the pharmacophore, especially the determination of the orientation of the nitrogen lone pair (NLP) related to the phenyl. On the other hand, electrostatic studies, combined with geometrical features, have allowed us to schematize the interaction mode of an active conformation to the binding site. Finally, studies of the molecular lipophilic potential (MLP) have provided us information on the position of lipophilic and hydrophilic zones of the pharmacophore.

MeSH terms

  • Binding Sites
  • Dioxolanes / chemistry
  • Dizocilpine Maleate / chemistry*
  • Dizocilpine Maleate / metabolism*
  • Excitatory Amino Acid Antagonists / chemistry*
  • Excitatory Amino Acid Antagonists / metabolism*
  • Ketamine / chemistry
  • Lipids / chemistry
  • Models, Molecular*
  • Molecular Structure
  • N-Methylaspartate / metabolism
  • Nitrogen / chemistry
  • Phencyclidine / chemistry
  • Piperidines / chemistry
  • Quinolines / chemistry
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / chemistry
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Static Electricity

Substances

  • Dioxolanes
  • Excitatory Amino Acid Antagonists
  • Lipids
  • Piperidines
  • Quinolines
  • Receptors, N-Methyl-D-Aspartate
  • 8a-phenyldecahydroquinoline
  • dioxadrol
  • N-Methylaspartate
  • Ketamine
  • Dizocilpine Maleate
  • Phencyclidine
  • dexoxadrol
  • Nitrogen