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An in silico approach to primaquine binding to Trp756 in the external vestibule of sodium channel Nav 1.4

Authors Scior T, Islas A, Martínez-Morales E, Cuanalo-Contreras K, Millan-Perezpeña L, Salinas-Stefanón EM

Published 26 July 2011 Volume 2011:4 Pages 41—48

DOI https://doi.org/10.2147/JRLCR.S20295

Review by Single-blind

Peer reviewer comments 4


Thomas F Scior1, Angel A Islas2, Evelyn Martínez-Morales2, Karina Cuanalo-Contreras1, Lourdes Millan-Perezpeña3, Eduardo M Salinas-Stefanón2
1Departamento de Farmacia, 2Instituto de Fisiología, 3Centro de Química Instituto de Ciencias, Benemérita Universidad Autónoma de Puebla, Puebla, Puebla, México

Abstract: The aim of our computed study was to examine the possible binding site of primaquine (PQ) using a combined homology protein modeling, automated docking, and experimental approach. The target models of wild type and mutant types of the voltagedependent sodium channel in rat skeletal muscle (rNav 1.4) were based on previous work by other researchers. Docking was carried out on the P-loop in the structural model of the rNav 1.4 channel, in the open state configuration, to identify those amino acidic residues important for PQ binding. The three-dimensional models of the P-loop segment of wild types and mutant types (W402, W756C, W1239C, and W1531A at the outer tryptophan-rich lip, as well as D400C, E755C, K1237C, and A1529C of the DEKA motif) helped us to identify residues playing key roles in aminoquinoline binding. In good agreement with experimental results, a 1000-fold inhibition loss was observed. Tryptophan 756 is crucial for the reversible blocking effects of PQ. As a result, mutant-type W756C abolished the blocking effect of PQ in voltage-clamp assays.

Keywords:
computer docking, homology modeling, Nav 1.4, sodium channel, oocytes, primaquine (PQ), site-directed mutagenesis, voltage clamp
 

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