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

: Agnieszka A. Kaczor, Zbigniew Karczmarzyk, Andrzej Fruziński, Kalevi Pihlaja, Jari Sinkkonen, Kirsti Wiinämaki, Christiane Kronbach, Klaus Unverferth, Antti Poso, Dariusz Matosiuk

Publisher: PERGAMON-ELSEVIER SCIENCE LTD

: OXFORD; THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND

: 2014

: Bioorganic and Medicinal Chemistry

: Bioorganic & medicinal chemistry

: Bioorg.Med.Chem.

: 22

: 2

: 787

: 795

: 9

: 0968-0896

DOI: https://doi.org/10.1016/j.bmc.2013.12.013

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. (C) 2013 Elsevier Ltd. All rights reserved.