In silico docking reveals possible Riluzole binding sites on Nav1.6 sodium channel: implications for drug design strategy on Amyotrophic Lateral Sclerosis

Abstract

Event Abstract Back to Event In silico docking reveals possible Riluzole binding sites on Nav1.6 sodium channel: implications for drug design strategy on Amyotrophic Lateral Sclerosis Omar Sierra1*, Janneth González1 and George Barreto1 1 Pontificia Universidad Javeriana, Colombia Amyotrophic Lateral Sclerosis (ALS) is a progressive neuromuscular disorder involving primarily motor neurons (Hoffman 2008). Glutamate excitotoxicity has been suggested to contribute to this progressive loss of motor neurons due to astrocytes reduced ability to uptake this neurotransmitter (Van Den Bosch 2006). Previous reports revealed that the Na+ channel blockade may increase motor neurons survival against excitotoxic death by targeting the Sodium channel protein Nav1.6 (Hebert et al. 1994). Riluzole interferes with glutamate-mediated transmission, thereby reducing excitotoxicity (Tavakoli 2002). These effects may be partly due to inactivation of voltage-dependent sodium channels Nav1.6 (Ajroud-Driss et al. 2007), suggesting an indirect effect of this drug on glutamate transporters. However many concerns are still unresolved due to experimental caveats, the lack of significant theoretical guidance (Fu et al. 2002) and experimental data on the structure of Riluzole-VGSc complexes. In this study, we have integrated a docking analysis and homology modeling to understand the association of Riluzole with the alpha subunit of voltage-gated sodium channel Nav 1.6. First, we have constructed the three-dimensional structure model for the voltage-gated sodium channel subunit alpha Nav1.6 via homology modeling. Our results demonstrate that Riluzole interacts with the Nav1.6 channel, more specifically in the key residues TYR 1787, LEU 1843 and GLN 1799, suggesting possible cellular implications driven by these amino acids on Riluzole-Nav1.6 interaction, which may serve as an important output for a more specific and experimental drug design therapy against ALS References. Ajroud-Driss S, et al. 2007. Riluzole metabolism and CYP1A1/2 polymorphisms in patients with ALS. Amyotroph Lateral Scler 8: 305-309. Hebert T, Drapeau P, Pradier L, Dunn R. 1994. Block of the rat brain IIA sodium channel alpha subunit by the neuroprotective drug riluzole. Molecular pharmacology 45: 1055-1060. Hoffman JJ. 2008. Toward a better understanding of amyotrophic lateral sclerosis. Home Healthc Nurse 26: 337-342; quiz 343-334. Tavakoli M. 2002. Disease progression in amyotrophic lateral sclerosis. Identifying the cost-utility of riluzole by disease stage. The european journal health economycs 3: 156-165. Van Den Bosch L, Van Damme, P., Bogaert, E., & Robberecht, W. . 2006.amyotrophic lateral sclerosis. Biochimica Et Biophysica Acta - Mol ecular Basis of Disease: 1762(1711–1712) 1068-1082 Keywords: computational neuroscience, Amyotrophic lateral sclerosis (ALS), glutamate excitotoxicity, 3D structure, nav1.6 Conference: 5th INCF Congress of Neuroinformatics, Munich, Germany, 10 Sep - 12 Sep, 2012. Presentation Type: Poster Topic: Neuroinformatics Citation: Sierra O, González J and Barreto G (2014). In silico docking reveals possible Riluzole binding sites on Nav1.6 sodium channel: implications for drug design strategy on Amyotrophic Lateral Sclerosis. Front. Neuroinform. Conference Abstract: 5th INCF Congress of Neuroinformatics. doi: 10.3389/conf.fninf.2014.08.00078 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 21 Mar 2013; Published Online: 27 Feb 2014. * Correspondence: Dr. Omar Sierra, Pontificia Universidad Javeriana, BOGOTA, Colombia, osierra@javeriana.edu.co Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Omar Sierra Janneth González George Barreto Google Omar Sierra Janneth González George Barreto Google Scholar Omar Sierra Janneth González George Barreto PubMed Omar Sierra Janneth González George Barreto Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.