Protonation state of inhibitors determines interaction sites within voltage-gated sodium channels

Proceedings of the National Academy of Sciences of the United States of America
Amanda BuyanBen Corry

Abstract

Voltage-gated sodium channels are essential for carrying electrical signals throughout the body, and mutations in these proteins are responsible for a variety of disorders, including epilepsy and pain syndromes. As such, they are the target of a number of drugs used for reducing pain or combatting arrhythmias and seizures. However, these drugs affect all sodium channel subtypes found in the body. Designing compounds to target select sodium channel subtypes will provide a new therapeutic pathway and would maximize treatment efficacy while minimizing side effects. Here, we examine the binding preferences of nine compounds known to be sodium channel pore blockers in molecular dynamics simulations. We use the approach of replica exchange solute tempering (REST) to gain a more complete understanding of the inhibitors' behavior inside the pore of NavMs, a bacterial sodium channel, and NavPas, a eukaryotic sodium channel. Using these simulations, we are able to show that both charged and neutral compounds partition into the bilayer, but neutral forms more readily cross it. We show that there are two possible binding sites for the compounds: (i) a site on helix 6, which has been previously determined by many experimental and computatio...Continue Reading

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Citations

Jul 19, 2018·The Journal of General Physiology·Elaine YangManuel Covarrubias
Jul 11, 2020·Journal of Computer-aided Molecular Design·Denis B TikhonovBoris S Zhorov
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