title: Docking Simulation of the Binding Interactions of Saxitoxin Analogs Produced by the Marine Dinoflagellate Gymnodinium catenatum to the Voltage-Gated Sodium Channel Nav1.4.
abstract: Saxitoxin (STX) and its analogs are paralytic alkaloid neurotoxins that block the voltage-gated sodium channel pore (Nav), impeding passage of Na⁺ ions into the intracellular space, and thereby preventing the action potential in the peripheral nervous system and skeletal muscle. The marine dinoflagellate Gymnodinium catenatum produces an array of such toxins, including the recently discovered benzoyl analogs, for which the mammalian toxicities are essentially unknown. We subjected STX and its analogs to a theoretical docking simulation based upon two alternative tri-dimensional models of the Nav1.4 to find a relationship between the binding properties and the known mammalian toxicity of selected STX analogs. We inferred hypothetical toxicities for the benzoyl analogs from the modeled values. We demonstrate that these toxins exhibit different binding modes with similar free binding energies and that these alternative binding modes are equally probable. We propose that the principal binding that governs ligand recognition is mediated by electrostatic interactions. Our simulation constitutes the first in silico modeling study on benzoyl-type paralytic toxins and provides an approach towards a better understanding of the mode of action of STX and its analogs.
authors.affiliation: Departamento de Plancton y Ecología Marina, Centro Interdisciplinario de Ciencias Marinas-Instituto Politécnico Nacional, La Paz, B. C. S. 23096, Mexico. lorena.duran@awi.de.
authors.forename: Lorena M
authors.initials: LM
authors.lastname: Durán-Riveroll
authors.affiliation: Alfred-Wegener-Institut, Helmholtz Zentrum für Polar-und Meeresforschung, Bremerhaven 27570, Germany. allan.cembella@awi.de.
authors.forename: Allan D
authors.initials: AD
authors.lastname: Cembella
authors.affiliation: Departamento de Plancton y Ecología Marina, Centro Interdisciplinario de Ciencias Marinas-Instituto Politécnico Nacional, La Paz, B. C. S. 23096, Mexico. cbands@ipn.mx.
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Band-Schmidt
authors.affiliation: Centro de Investigaciones Biológicas del Noroeste, La Paz, B.C.S. 23201, Mexico. jose04@cibnor.mx.
authors.forename: José J
authors.initials: JJ
authors.lastname: Bustillos-Guzmán
authors.affiliation: Laboratorio de Modelado Molecular y Diseño de Fármacos, Escuela Superior de Medicina-Instituto Politécnico Nacional, Mexico City 11340, Mexico. jcorreab@ipn.mx.
authors.forename: José
authors.initials: J
authors.lastname: Correa-Basurto
mesh_terms: D004141:Dinoflagellida / Q000378:metabolism; D062105:Molecular Docking Simulation; D062553:NAV1.4 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000378:metabolism*; D012530:Saxitoxin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D062553:NAV1.4 Voltage-Gated Sodium Channel; D012530:Saxitoxin
keywords: benzoyl saxitoxin analogs; binding affinity; molecular docking; voltage-gated sodium channel