Structural studies, homology modeling and molecular docking of novel non-competitive antagonists of GluK1/GluK2 receptors

Bioorg Med Chem. 2014 Jan 15;22(2):787-95. doi: 10.1016/j.bmc.2013.12.013. Epub 2013 Dec 12.

Abstract

Non-competitive ligands of kainate receptors have focused significant attention as medicinal compounds because they seem to be better tolerated than competitive antagonists and uncompetitive blocker of these receptors. Here we present structural studies (X-ray structure determination, NMR and MS spectra) of novel indole-derived non-competitive antagonists of GluK1/GluK2 receptors, homology models of GluK1 and GluK2 receptors based on novel AMPA receptor template as well as molecular docking of ligands to their molecular targets. We find that the allosteric site is in the receptor transduction domain, in one receptor subunit, not between the two subunits as it was indicated by our earlier studies.

Keywords: Homology modeling; Indole derivatives; Kainate receptors; Molecular docking; X-ray structure determination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • GluK2 Kainate Receptor
  • Humans
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Receptors, Kainic Acid / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Gluk1 kainate receptor
  • Indoles
  • Receptors, Kainic Acid