Functionalized Fullerene Targeting Human Voltage-Gated Sodium Channel, hNa v 1.7.

Mutations of hNav 1.7 that cause its activities to be enhanced contribute to severe neuropathic pain. Only a small number of hNav 1.7 specific inhibitors have been identified, most of which interact with the voltage-sensing domain of the voltage-activated sodium ion channel. In our previous computational study, we demonstrated that a [Lys6 ]-C84 fullerene binds tightly (affinity of 46 nM) to Nav Ab, the voltage-gated sodium channel from the bacterium Arcobacter butzleri. Here, we extend this work and, using molecular dynamics simulations, demonstrate that the same [Lys6 ]-C84 fullerene binds strongly (2.7 nM) to the pore of a modeled human sodium ion channel hNav 1.7. In contrast, the fullerene binds only weakly to a mutated model of hNav 1.7 (I1399D) (14.5 mM) and a model of the skeletal muscle hNav 1.4 (3.7 mM). Comparison of one representative sequence from each of the nine human sodium channel isoforms shows that only hNav 1.7 possesses residues that are critical for binding the fullerene derivative and blocking the channel pore.