Functionalized Fullerene Targeting Human Voltage-Gated Sodium Channel, hNa_v1.7

Mutations of hNa_v1.7 that cause its activities to be enhanced contribute to severe neuropathic pain. Only a small number of hNa_v1.7 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 Na_vAb, 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 hNa_v1.7. In contrast, the fullerene binds only weakly to a mutated model of hNa_v1.7 (I1399D) (14.5 mM) and a model of the skeletal muscle hNa_v1.4 (3.7 mM). Comparison of one representative sequence from each of the nine human sodium channel isoforms shows that only hNa_v1.7 possesses residues that are critical for binding the fullerene derivative and blocking the channel pore.