Sodium Channel/Ligand Complex Structures as a Guide for Rational Drug Design

The initiation of the action potential in excitable cells results from the opening of voltage-gated sodium channels. These channels represent key targets for development of pharmaceutical drugs as mutations in human sodium channels produce a wide range of neurological and cardiovascular diseases. Channel blockers such as lamotrigine and lidocaine have been shown to have efficacy, respectively, as anti-epileptic and local anaesthetic drugs, and are widely used clinically. We have shown that these and other drugs and ligands which block human sodium channels also bind to and block the NavMs channel (a prokaryotic orthologue of human sodium channels) with similar affinities and kinetics. We have determined the crystal structures of several open pore forms of NavMs in complex with human drugs and other channel blockers, and have further examined their interactions with these channels using circular dichroism spectroscopy and molecular modelling methods. The binding sites we have identified have been validated by both structure and function studies on designed mutants. This information should be valuable for the design of new specific and selective drugs.