Molecular modeling annual

, Volume 8, Issue 2, pp 65–72

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

  • Menana Elhallaoui
  • Michel Laguerre
  • Alain Carpy
  • Fouad Chahdi Ouazzani
Original Paper

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.

Keywords. Noncompetitive antagonists – NMDA receptor – Pharmacophore – Conformational analysis – MEP – MLP 

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Copyright information

© Springer-Verlag 2002

Authors and Affiliations

  • Menana Elhallaoui
    • 1
  • Michel Laguerre
    • 2
  • Alain Carpy
    • 2
  • Fouad Chahdi Ouazzani
    • 1
  1. 1.Département de chimie, Faculté des sciences et techniques, Fès-Saïss Université Sidi Mohamed Ben Abdellah, B.P.2202 Route D'Immouzzer, Fès, Morocco e-mail: m.elhallaoui@caramail.comMA
  2. 2.ER61 CNRS, UFR des sciences Pharmaceutiques, Université de Bordeaux II 3, Place de la Victoire, 33076 Bordeaux Cedex, FranceFR

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