Evaluating the ligands' potency to modulate the fast inactivation of voltage-gated sodium channel.

Electrical impulse transmission along the nerve fiber in the form of the action potential is possible due to fast conformational changes of voltage-gated sodium channels (Nav) that control the sodium ions flow into the cell. The transition between functional states, called the gating mechanism, can be modulated by natural toxins and drugs. Here, we propose to use steered molecular dynamics (SMD) to investigate the ability of various ligands to impact the gating of P. americana cockroach Nav. By calculating mechanical forces required to relocate the inactivation particle to its binding pocket or to dislocate it, we assessed ligands' efficacy in trapping a channel in a given state (open or fast inactivated). Importantly, we showed that sulfonamide PF-05089771 and phospholipid PIP2 act as insect Nav channels inhibitors. We confirmed the ligands' action by electrophysiological measurements of their ability to modulate the neural activity. Our approach, applied here on a cockroach channel, can be used in any other Nav, i.g, as a step in computational-based drug screening to evaluate new drug candidates.