Binding modes of noncompetitive AMPA antagonists: a computational approach

Farmaco. 2003 Feb;58(2):107-13. doi: 10.1016/s0014-827x(02)00027-7.

Abstract

The activity of functional AMPA receptors (AMPARs) is modulated by noncompetitive antagonists. So far, no information about the molecular mechanism of action and the localization of the binding pocket(s) is available. We speculated that the leucine/isoleucine/valine binding protein (LIVBP)-like domain of AMPAR, localized at the extracellular N-terminus of the receptor, might be involved in the binding of noncompetitive antagonists and we tested this hypothesis through a computational approach involving the comparison with NMDA and metabotropic glutamate receptors and the generation of a 3D homology model of the LIVBP-like domain of AMPAR. The results suggest that the interdomain cleft of the LIVBP-like domain of AMPAR may contain the noncompetitive antagonist binding pocket.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Binding Sites / drug effects
  • Binding Sites / physiology
  • Computational Biology / methods*
  • Excitatory Amino Acid Antagonists / chemistry*
  • Excitatory Amino Acid Antagonists / metabolism
  • Molecular Sequence Data
  • Receptors, AMPA / antagonists & inhibitors*
  • Receptors, AMPA / chemistry*
  • Receptors, AMPA / metabolism

Substances

  • Excitatory Amino Acid Antagonists
  • Receptors, AMPA