INS Topical Seminar – Boris Zhorov (Hamilton and St. Petersburg)
“Computational Structural Pharmacology and Toxicology of Voltage-Gated Sodium Channels”
Voltage-gated sodium channels are targets for many toxins and medically important drugs. Despite decades of intensive studies in industry and academia, atomic mechanisms of action are still not completely understood. The major cause is a lack of high-resolution structures of mammalian channels and their complexes with ligands. In these circumstances a useful approach is homology modeling that employs as templates available X-ray and cryo-EM structures of homologous P-loop channels. On one hand, due to inherent limitations of this approach, results should be treated with caution. In particular, models should be tested against relevant experimental data. On the other hand, docking of drugs and toxins in homology models provides a unique possibility to integrate diverse experimental data provided by mutational analysis, electrophysiology and studies of structure-activity relations.
Computational modeling advanced our understanding of mechanisms of several classes of ligands. These include tetrodotoxin and mu-conotoxins that block the outer pore, local anesthetics that block of the inner pore, batrachotoxin that binds in the inner pore but, paradoxically, activates the channel, pyrethroid insecticides that activate the channel by binding at lipid-exposed repeat interfaces, and scorpion alpha and beta-toxins, which bind between the pore and voltage-sensing domains and modify the channel gating.
For any question, feel free to contact:
Benjamin Morillon (firstname.lastname@example.org) or Adam Williamson (adam.WILLIAMSON@univ-amu.fr)