Simulating the Access and Binding of Subtype Selective Sodium Channel Inhibitors

Abstract

Sodium channel blockers are commonly used as local anaesthetics, antiarrhythmics and anti-epileptics, however they generally cannot distinguish between the different sodium channel subtypes expressed in humans. The development of highly selective channel inhibitors will allow for a range of new clinical applications and a decrease in side effects. To help achieve this aim we here examine how two recently discovered subtype selective voltage sensor inhibitors interact with a bacterial sodium channel (NavAb) and with the eukaryotic channel Nav1.7 (as part of a Nav1.7/NavAb chimera). Using a range of advanced sampling techniques and tens of ms of molecular dynamics simulations we show both where these compounds bind and how they access this site. Our simulations help unravel how subtype selectivity is achieved and are able to accurately predict the binding affinity in each channel. This highlights that for these compounds binding is much weaker for bacterial channels than for Nav1.7. The simulations also answer the puzzle as to why the channels have to be held in the inactivated state for prolonged periods in order to measure inhibition, as the compounds face large barriers to access the binding site due to specific interactions with the protein. These results will assist in developing strategies to speed up the kinetics of inhibition and to improve selectivity of the inhibitors for specific sodium channel subtypes. Show more