Mechanism of sodium channel block by local anesthetics, antiarrhythmics, and anticonvulsants

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. Her...

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Vydané v:	The Journal of general physiology Ročník 149; číslo 4; s. 465
Hlavní autori:	Tikhonov, Denis B, Zhorov, Boris S
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 03.04.2017
Predmet:	Acetamides - pharmacology Anesthetics, Local - pharmacology Animals Anti-Arrhythmia Agents - pharmacology Anticonvulsants - pharmacology Benzhydryl Compounds - pharmacology Binding Sites Carbamazepine - pharmacology Cocaine - pharmacology Humans Lacosamide Lamotrigine Lidocaine - analogs & derivatives Lidocaine - pharmacology Molecular Docking Simulation NAV1.4 Voltage-Gated Sodium Channel - chemistry NAV1.4 Voltage-Gated Sodium Channel - metabolism Phenols - pharmacology Phenytoin - pharmacology Piperazines - pharmacology Protein Binding Pyrimidines - pharmacology Quinidine - pharmacology Sodium Channel Blockers - pharmacology Triazines - pharmacology
ISSN:	1540-7748, 1540-7748
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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.
AbstractList	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. 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.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.
Author	Zhorov, Boris S Tikhonov, Denis B
Author_xml	– sequence: 1 givenname: Denis B surname: Tikhonov fullname: Tikhonov, Denis B organization: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8S4L8, Canada – sequence: 2 givenname: Boris S orcidid: 0000-0002-3630-7114 surname: Zhorov fullname: Zhorov, Boris S email: zhorov@mcmaster.ca organization: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8S4L8, Canada
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SubjectTerms	Acetamides - pharmacology Anesthetics, Local - pharmacology Animals Anti-Arrhythmia Agents - pharmacology Anticonvulsants - pharmacology Benzhydryl Compounds - pharmacology Binding Sites Carbamazepine - pharmacology Cocaine - pharmacology Humans Lacosamide Lamotrigine Lidocaine - analogs & derivatives Lidocaine - pharmacology Molecular Docking Simulation NAV1.4 Voltage-Gated Sodium Channel - chemistry NAV1.4 Voltage-Gated Sodium Channel - metabolism Phenols - pharmacology Phenytoin - pharmacology Piperazines - pharmacology Protein Binding Pyrimidines - pharmacology Quinidine - pharmacology Sodium Channel Blockers - pharmacology Triazines - pharmacology
Title	Mechanism of sodium channel block by local anesthetics, antiarrhythmics, and anticonvulsants
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