Physical basis of specificity and delayed binding of a subtype selective sodium channel inhibitor

Ben Corry

doi:10.1038/s41598-018-19850-9

Abstract

Nerve and muscle signalling is controlled by voltage-gated sodium (Nav) channels which are the targets of local anesthetics, anti-epileptics and anti-arrythmics. Current medications do not selectively target specific types of Nav found in the body, but compounds that do so have the potential to be breakthrough treatments for chronic pain, epilepsy and other neuronal disorders. We use long computer simulations totaling more than 26 μs to show how a promising lead compound can target one Nav implicated in pain perception and specific channels found in bacteria, and accurately predict the affinity of the compound to different channel types. Most importantly, we provide two explanations for the slow kinetics of this class of compound that limits their therapeutic utility. Firstly, the negative charge on the compound is essential for high affinity binding but is also responsible for energetic barriers that slow binding. Secondly, the compound has to undergo a conformational reorientation during the binding process. This knowledge aids the design of compounds affecting specific eukaryotic and bacterial channels and suggests routes for future drug development.

Highlights

Voltage gated sodium channels (Navs) initiate action potentials in excitable cells by opening in response to small depolarising signals to allow for rapid influx of Na+ into the cell
The aryl sulfanomide compounds PF-0485626420, (Fig. 1) PF-05089771 and PF-0519800740,41 have recently been described as subtype selective sodium channel inhibitors, having low nm IC50 for Nav1.7 and greater than ten-fold weaker affinity for all other Navs
More recently the location of binding of a PFZ analogue to a chimeric sodium channel in which a eukaryotic voltage sensing domain was attached to a bacterial pore domain (Nav1.7/NavAb chimera) was characterised using X-ray crystallography[34]

Summary

Introduction

Voltage gated sodium channels (Navs) initiate action potentials in excitable cells by opening in response to small depolarising signals to allow for rapid influx of Na+ into the cell. PFZ and analogues have been shown by mutation studies to bind to the extracellular side of the voltage sensor[20,40], an area with greater sequence diversity than the central pore, making this an attractive lead for developing subtype selective channel modulating compounds.

Results

Conclusion