An in silico approach to primaquine binding to Trp756 in the external vestibule of sodium channel Nav 1.4
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
© 2011 The Author(s). This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.