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Free-binding energies and molecular interactions of yessotoxin in the voltage-gated sodium channel NaV1.5: an in silico approach
1 , * 2, 3 , 3 , 1
1  Laboratorio de Diseño y Desarrollo de Nuevos Fármacos e Innovación Biotecnológica, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México, Mexico
2  CONACyT-Departamento de Biotecnología Marina, Centro de Investigación Científica y de Educación Superior de Ensenada, B.C. Ensenada, Baja California, México
3  Alfred-Wegener-Institut, Helmholtz-Zentrum für Polar-und Meeresforschung, Bremerhaven, Germany

Published: 14 January 2021 by MDPI in 1st International Electronic Conference on Toxins session Poster

Several marine dinoflagellates produce unique secondary metabolites with intriguing biological activities, eliciting anticancer, antiepileptic, anti-inflammatory, or anti-microbial responses in various cell types. Among these known compounds are phycotoxins, such as the linear and cyclic polyethers considered as potential therapeutants due to their complex alternative mode of action as ion-channel effectors or enzyme inhibitors capable of modifying diverse intracellular signaling pathways. Yessotoxin (YTX) and analogs are polyketide-derived polycyclic toxins produced by certain species of marine dinoflagellates, Protoceratium reticulatum, Lingulodinium polyedra, and Gonyaulax spinifera, and are structurally related to ciguatoxins and brevetoxins with potent ion-channel activity. The over-expression or aberrant function of ion channels is considered a channelopathy, and critical pathologies in different intracellular signaling pathways that involve receptors such as voltage-gated ion-channels, particularly voltage-gated sodium channels (NaV), are exhibited in response to exposure to such toxins. In the search for innovative therapeutants, this study aimed to evaluate the affinity of YTX for the NaV1.5 channel, using in silico modelling tools. This approach allowed for identification of these interactions and determination of the respective free-binding energies. Our results showed significant interactions and low binding free energies (ΔG), between -6.79 and -10.32 Kcal mol-1 for YTX in the NaV1.5 protein model. Certain amino acid residues in Domains I and II were reached, indicating that this toxin is a potential NaV 1.5 modulator. This study constitutes the first approach to in silico exploration of polyketide-derived dinoflagellate toxins in pursuit of evaluating their therapeutic potential.

Keywords: biological activity; free-binding energy; ion channel modulator; molecular docking