%0 Journal Article
%T An in silico approach to primaquine binding to Trp756 in the external vestibule of sodium channel Nav 1.4
%A Scior TF
%A Islas AA
%A Mart&iacute
%A nez-Morales E
%A Cuanalo-Contreras K
%J Journal of Receptor, Ligand and Channel Research
%D 2011
%I 
%X Thomas F Scior1, Angel A Islas2, Evelyn Mart¨ªnez-Morales2, Karina Cuanalo-Contreras1, Lourdes Millan-Perezpe a3, Eduardo M Salinas-Stefan¨®n21Departamento de Farmacia, 2Instituto de Fisiolog¨ªa, 3Centro de Qu¨ªmica Instituto de Ciencias, Benem¨¦rita Universidad Aut¨®noma de Puebla, Puebla, Puebla, M¨¦xicoAbstract: 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
%U http://www.dovepress.com/an-in-silico-approach-to-primaquine-binding-to-trp756-in-the-external--a7949