Search for content and authors
 

Pharmacophore model of group II metabotropic glutamate receptor modulators

Mateusz Sikora ,  Mateusz Nowak 

Polish Academy of Sciences, Institute of Pharmacology, Department of Medicinal Chemistry, Smętna 12, Kraków 31-343, Poland

Abstract
Metabotropic glutamate receptors (mgluRs) are members of large G-protein coupled receptor (GPCR) family, activated by L-glutamate, an excitatory neurotransmitter. They are responsible for normal signal transduction in central nervous system as well as patophysiological processes. No crystal structure of complete metabotropic glutamate receptor is known so far, although it is believed, that all mgluRs manifest similar three-dimensional organization. They consist of large extracellular domain with glutamate binding site, a cysteine-rich linker and typical for GPCR's trans-helical domain containing allosteric site [1]. mGluR group II receptors are potential targets for anti-schizophrenic drugs, as well as for generalised anxiety disorder [2]. The orthosteric ligand binding site has been extensively studied and shown limited usability as a drug target, because of marginal selectivity between receptor types. Another, allosteric binding site located on extracellular part of trans-membrane domain exhibits more diversity, and thus specificity. The search for mgluR modulators (i.e. compounds showing the affinity to allosteric site) yielded vast amount of pharmacological data, facilitating computer-assisted approaches. Until today, pharmacophore models for metabotropic glutamate receptors has been elucidated only for mGluR I [3].
We created a pharmacophore model of positive mGluR II modulator using openly available bio-assay results. For creating a 3-D model we utilized Catalyst software from Accelrys. Some key interactions responsible for binding and specificity were proposed. The mapping of pharmacophore on the 3D model of the binding site is also presented.

References:
[1] Current Opinion in Neurobiology 2003, 13(3): 271-278
[2] Nature Medicine 2007, 13: 1102-1107
[3] J. Med. Chem. 2008, 51: 634-647

 

Legal notice
  • Legal notice:

    Copyright (c) Pielaszek Research, all rights reserved.
    The above materials, including auxiliary resources, are subject to Publisher's copyright and the Author(s) intellectual rights. Without limiting Author(s) rights under respective Copyright Transfer Agreement, no part of the above documents may be reproduced without the express written permission of Pielaszek Research, the Publisher. Express permission from the Author(s) is required to use the above materials for academic purposes, such as lectures or scientific presentations.
    In every case, proper references including Author(s) name(s) and URL of this webpage: https://science24.com/paper/14857 must be provided.

 

Related papers
  1. Molecular modeling explains differences in binding affinity of new potent and selective 5-HT1A ligands: arylpiperazinylalkylthiobenzoxazole derivatives

Presentation: Poster at VI Multidyscyplinarna Konferencja Nauki o Leku, by Mateusz Nowak
See On-line Journal of VI Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2008-03-27 22:25
Revised:   2009-06-07 00:48