Abstract

Voltage-gated sodium (Na⁺) channels are targets for local anesthetic (LA) drugs that bind in the inner pore of the channel with affinities related to the channel gating states. Our core model of the sodium channel (P loops and S5 and S6 segments from each of the four domains) was closed because it was developed using coordinates from the KcsA channel crystallographic structure. We developed a model of the activated, open channel based on the structure of the open MthK channel, which was characterized by bends at the S6 glycine or serine residues. This created a conformation that allowed energetically appropriate docking of the LA drugs. The alkylamino head of ionizable LA molecules was docked closer to the selectivity filter and in association with Phe-1579 of IVS6 and Leu-1280 of IIIS6 (Nav1.4), and the aromatic ring interacted with Tyr-1586 of IVS6 and Asn-434 of IS6. Comparison of multiple LA drugs showed relative binding affinities in the model consistent with experimental studies. The ionizable LA alkylamino heads interact primarily by van der Waals forces that position the charge so as to create a positive electrostatic barrier for cation permeation. Permanently uncharged benzocaine could be docked in the closed conformation as well, stabilizing the closed conformation. The structurally different anticonvulsant lamotrigine and one of its derivatives have a binding site that fully overlaps with that of the LA drugs. The open, activated channel creates the high-affinity binding site for these sodium channel blocker drugs, and block may be mainly electrostatic.