title: Mechanism of sodium channel block by local anesthetics, antiarrhythmics, and anticonvulsants.
abstract: Local anesthetics, antiarrhythmics, and anticonvulsants include both charged and electroneutral compounds that block voltage-gated sodium channels. Prior studies have revealed a common drug-binding region within the pore, but details about the binding sites and mechanism of block remain unclear. Here, we use the x-ray structure of a prokaryotic sodium channel, NavMs, to model a eukaryotic channel and dock representative ligands. These include lidocaine, QX-314, cocaine, quinidine, lamotrigine, carbamazepine (CMZ), phenytoin, lacosamide, sipatrigine, and bisphenol A. Preliminary calculations demonstrated that a sodium ion near the selectivity filter attracts electroneutral CMZ but repels cationic lidocaine. Therefore, we further docked electroneutral and cationic drugs with and without a sodium ion, respectively. In our models, all the drugs interact with a phenylalanine in helix IVS6. Electroneutral drugs trap a sodium ion in the proximity of the selectivity filter, and this same site attracts the charged group of cationic ligands. At this position, even small drugs can block the permeation pathway by an electrostatic or steric mechanism. Our study proposes a common pharmacophore for these diverse drugs. It includes a cationic moiety and an aromatic moiety, which are usually linked by four bonds.
authors.affiliation: Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 194223 St. Petersburg, Russia.|Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8S4L8, Canada.
authors.forename: Denis B
authors.initials: DB
authors.lastname: Tikhonov
authors.affiliation: Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 194223 St. Petersburg, Russia zhorov@mcmaster.ca.|Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8S4L8, Canada.
authors.forename: Boris S
authors.identifier: http://orcid.org/0000-0002-3630-7114
authors.initials: BS
authors.lastname: Zhorov
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D000927:Anticonvulsants / Q000494:pharmacology*; D001559:Benzhydryl Compounds / Q000494:pharmacology; D001665:Binding Sites; D002220:Carbamazepine / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D006801:Humans; D000078334:Lacosamide; D000077213:Lamotrigine; D008012:Lidocaine / Q000031:analogs & derivatives / Q000494:pharmacology; D062105:Molecular Docking Simulation; D062553:NAV1.4 Voltage-Gated Sodium Channel / Q000737:chemistry* / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology; D010672:Phenytoin / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding; D011743:Pyrimidines / Q000494:pharmacology; D011802:Quinidine / Q000494:pharmacology; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D014227:Triazines / Q000494:pharmacology; D000098826:Bisphenol A Compounds
chemical_list: D000081:Acetamides; D000779:Anesthetics, Local; D000889:Anti-Arrhythmia Agents; D000927:Anticonvulsants; D001559:Benzhydryl Compounds; D002220:Carbamazepine; D003042:Cocaine; D000078334:Lacosamide; D000077213:Lamotrigine; D008012:Lidocaine; D062553:NAV1.4 Voltage-Gated Sodium Channel; D010636:Phenols; D010672:Phenytoin; D010879:Piperazines; D011743:Pyrimidines; D011802:Quinidine; D026941:Sodium Channel Blockers; D014227:Triazines; C012647:QX-314; C006780:bisphenol A; D000098826:Bisphenol A Compounds; C081980:sipatrigine