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Mol Inform. 2012 Sep;31(9):643-57. doi: 10.1002/minf.201200025. Epub 2012 Sep 7.

Harnessing Human N-type Ca(2+) Channel Receptor by Identifying the Atomic Hotspot Regions for Its Structure-Based Blocker Design.

Author information

1
Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160 062, India phone: +91-172-2214682, fax: 0091-172-2214692.
2
Present address: Amrita Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Ponekkara, Kochi-682 041, Kerala State, India phone: +91-484-4008769, fax: +91-484-2802120.
3
Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160 062, India phone: +91-172-2214682, fax: 0091-172-2214692,. cgopimohan@yahoo.com, cgmohan@aims.amrita.edu.
4
Present address: Amrita Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Ponekkara, Kochi-682 041, Kerala State, India phone: +91-484-4008769, fax: +91-484-2802120. cgopimohan@yahoo.com, cgmohan@aims.amrita.edu.

Abstract

The voltage dependent N-type Ca(2+) channel (NCC) receptor was identified to have therapeutic potential for the treatment of neuropathic pain and stroke disease. The Ca(2+) ion transport through the transmembrane influx is mainly dependent on the closing, opening, or intermediate state gating mechanism of NCC. Harnessing this dynamic gating mechanism at the structural level is an important and challenging physiological phenomenon. The three dimensional (3D) structure of this membrane receptor is not yet experimentally determined to understand its mechanism of action. Based on these observations, we have developed for the first time the structure of the closed state of the NCC receptor at the pore forming domains which mainly involve three transmembrane helices (TMhs) S5, P and S6. Hot-spot binding site residues of this receptor model were identified by molecular docking technique using amlodipine, cilnidipine and nifedipine compounds known to be potent Ca(2+) channel antagonists. Further, the Ca(2+) ion permeability and the hydrophobic gating mechanism provided better structural and functional insights on the NCC receptor. These results are in consonance with other Ca(2+) channel receptors and would provide guidance for further biochemical investigations.

KEYWORDS:

Amlodipine; Ca2+ channel receptors; Homology model; Molecular docking; Pain

PMID:
27477815
DOI:
10.1002/minf.201200025

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