Temitayo O. Aiyelabola^1,, Sayantan Pradhan^2,, Takashiro Akitsu³

Voltage-gated sodium (Nav) channels are important pharmacological targets, with Nav1.7 playing a central role in pain signaling. Unlike conventional pore blockers, aryl sulfonamide gating modifiers target the voltage-sensing domain 4 (VSD4) through a state-dependent voltage-sensor trapping mechanism, preferentially interacting with the activated VSD4 and its R4 gating-charge residue. Targeting the relatively less-conserved VSD4 region may offer greater Nav1.7 isoform selectivity and reduced off-target effects. In this study, molecular docking was employed to investigate the interactions of two amide ligands and their corresponding copper(II) and cobalt(II) complexes with human Nav1.7 VSD4, using the selective VSD4 inhibitor GX-936 as a reference. Docking was performed using AutoDock following standard receptor and ligand preparation procedures. Among the investigated compounds, Cobalt Amide ligand 1 yielded the most negative docking score among the tested compounds. Cobalt Amide ligand 1 formed multiple predicted hydrogen-bonding electrostatic, π–π and hydrophobic interactions with key VSD4 residues, including Tyr1537, Trp1538, Arg1602, Arg1605, and particularly Arg1608, with a predicted electrostatic interaction distance of 4.48 Å. The better docking behavior of the cobalt complex may be associated with metal coordination-induced changes in molecular geometry, electronic distribution, and conformational properties. Overall, these findings identify Cobalt Amide ligand 1 as a promising candidate for further investigation as a Nav1.7 VSD4 modulator, with potential applications in the development of novel analgesic or anesthetic agents

Voltage-gated sodium channel, Nav1.7 molecular docking, amide ligand, copper complex, cobalt complex, local anesthetic