ArticlePLoS computational biology2014
Locating the route of entry and binding sites of benzocaine and phenytoin in a bacterial voltage gated sodium channel.
Article in PLoS computational biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 63 citations in OpenAlex.
- Phenytoin Derivatives as Antagonists of AMPA Receptors and Voltage-Gated Sodium Channels: A Structure-Function Study.International journal of molecular sciences · 2026Article
- Drugs exhibit diverse binding modes and access routes in the Nav1.5 cardiac sodium channel pore.The Journal of general physiology · 2025Article
- Inhibition of NMDA receptors and other ion channel types by membrane-associated drugs.Frontiers in pharmacology · 2025Review
- Article
- Toward Overcoming Pyrethroid Resistance in Mosquito Control: The Role of Sodium Channel Blocker Insecticides.International journal of molecular sciences · 2023Article
- P-Loop Channels: Experimental Structures, and Physics-Based and Neural Networks-Based Models.Membranes · 2022Review
- Characterizing fenestration size in sodium channel subtypes and their accessibility to inhibitors.Biophysical journal · 2022Article
- Computational methods and theory for ion channel research.Advances in physics: X · 2022Article
- Article
- Sodium Channels and Local Anesthetics-Old Friends With New Perspectives.Frontiers in pharmacology · 2022Review
- Inhibition of inflammatory pain and cough by a novel charged sodium channel blocker.British journal of pharmacology · 2021Article
- Molecular determinants of pro-arrhythmia proclivity of d- and l-sotalol via a multi-scale modeling pipeline.Journal of molecular and cellular cardiology · 2021Article
- Modelling of an autonomous Nav1.5 channel system as a part of in silico pharmacology study.Journal of molecular modeling · 2021Article
- Characterization of Compound-Specific, Concentration-Independent Biophysical Properties of Sodium Channel Inhibitor Mechanism of Action Using Automated Patch-Clamp Electrophysiology.Frontiers in pharmacology · 2021Article
- Article
- Inhibition of voltage-gated NaHeart rhythm O2 · 2020Article
- Challenges and Opportunities for Therapeutics Targeting the Voltage-Gated Sodium Channel Isoform NaJournal of medicinal chemistry · 2019Review
- Emerging Diversity in Lipid-Protein Interactions.Chemical reviews · 2019Review
- Comparison of permeation mechanisms in sodium-selective ion channels.Neuroscience letters · 2019Review
- Role of the Interaction Motif in Maintaining the Open Gate of an Open Sodium Channel.Biophysical journal · 2018Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Sodium channel blockers are used to control electrical excitability in cells as a treatment for epileptic seizures and cardiac arrhythmia, and to provide short term control of pain. Development of the next generation of drugs that can selectively target one of the nine types of voltage-gated sodium channel expressed in the body requires a much better understanding of how current channel blockers work. Here we make use of the recently determined crystal structure of the bacterial voltage gated sodium channel NavAb in molecular dynamics simulations to elucidate the position at which the sodium channel blocking drugs benzocaine and phenytoin bind to the protein as well as to understand how these drugs find their way into resting channels. We show that both drugs have two likely binding sites in the pore characterised by nonspecific, hydrophobic interactions: one just above the activation gate, and one at the entrance to the the lateral lipid filled fenestrations. Three independent methods find the same sites and all suggest that binding to the activation gate is slightly more favourable than at the fenestration. Both drugs are found to be able to pass through the fenestrations into the lipid with only small energy barriers, suggesting that this can represent the long posited hydrophobic entrance route for neutral drugs. Our simulations highlight the importance of a number of residues in directing drugs into and through the fenestration, and in forming the drug binding sites.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.