Functionalized Fullerene Targeting Human Voltage-Gated Sodium Channel, hNav1.7.

Abstract

Mutations of hNav1.7 that cause its activities to be enhanced contribute to severe neuropathic pain. Only a small number of hNav1.7 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 NavAb, 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 hNav1.7. In contrast, the fullerene binds only weakly to a mutated model of hNav1.7 (I1399D) (14.5 mM) and a model of the skeletal muscle hNav1.4 (3.7 mM). Comparison of one representative sequence from each of the nine human sodium channel isoforms shows that only hNav1.7 possesses residues that are critical for binding the fullerene derivative and blocking the channel pore.