Molecular model of anticonvulsant drug binding to the voltage-gated sodium channel inner pore.

ABSTRACT: The tricyclic anticonvulsant drugs phenytoin, carbamazepine, and lamotrigine block neuronal voltage-gated Na(+) channels, and their binding sites to domain IV-S6 in the channel's inner pore overlap with those of local anesthetic drugs. These anticonvulsants are neutral, in contrast to the mostly positively charged local anesthetics, but their open/inactivated-state blocking affinities are similar. Using a model of the open pore of the Na(+) channel that we developed by homology with the crystal structures of potassium channels, we have docked these three anticonvulsants with residues identified by mutagenesis as important for their binding energy. The three drugs show a common pharmacophore, including an aromatic ring that has an aromatic-aromatic interaction with Tyr-1771 of Na(V)1.2 and

SUBMITTER: Lipkind GM 

PROVIDER: S-EPMC2981395 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature