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

Molecular Pharmacology
Gregory M Lipkind, Harry A Fozzard

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 a polar amide or imide that interacts with the aromatic ring of Phe-1764 by a low-energy amino-aromatic hydrogen bond. The second aromatic ring is nearly at a right angle to the pharmacophore and fills the pore lumen, probably interacting with the other S6 segments and physically occluding the inner pore to block Na(+) permeation. Hydrophobic interactions with this second aromatic ring may contribute an important component to binding for antic...Continue Reading

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Citations

Oct 24, 2012·Journal of Medicinal Chemistry·Emma-Claire ElliottAndrew V Stachulski
Jul 16, 2013·Chemical Research in Toxicology·Yen LowAlexander Tropsha
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