Molecular dynamics simulations to characterise drug binding to voltage-gated sodium channels

Thomas, Frances Megan Rachel (2024) Molecular dynamics simulations to characterise drug binding to voltage-gated sodium channels. PhD thesis, Birkbeck, University of London.

Abstract

Voltage-gated sodium channels (Navs) are large integral membrane proteins which are responsible for the influx of sodium ions across the cell membrane into the cell. This influx of sodium ions is responsible for the upstroke of the action potential in electrically excitable cells. Multiple diseases have been linked to Nav dysfunction, including epilepsy, chronic pain and cardiac arrhythmia, making Navs drug targets. A bacterial Nav, NavMs (from Magnetococcus marinus) is used as a model for drug binding to human Navs. Riluzole, the current treatment for Amytrophic Lateral Sclerosis (ALS), is thought to interact directly with Navs and modulate sodium ion translocation. It has also been identified to bind NavMs and in this thesis, molecular dynamics simulations are presented to reproduce the location of the drug binding seen in a co-crystal structure, unveil the route of entry of riluzole, and to compare riluzole binding to NavMs and to a human Nav channel. Duloxetine is a small molecule drug prescribed as an antidepressant. This thesis presents a co-crystal structure of duloxetine bound to NavMs as well as molecular dynamics simulations to characterise duloxetine binding. This information contributes to our understanding of the binding site location and binding mechanism of these two drugs on Navs and enables investigations that could lead to their use in treatments of Nav diseases.

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