ArticleProceedings of the National Academy of Sciences of the United States of America2018
Protonation state of inhibitors determines interaction sites within voltage-gated sodium channels.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 49 citations in OpenAlex.
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- Inhibition of NMDA receptors and other ion channel types by membrane-associated drugs.Frontiers in pharmacology · 2025Review
- Membrane Permeation of Psychedelic Tryptamines by Dynamic Simulations.Biochemistry · 2024Article
- Therapeutic targeting of voltage-gated sodium channel NaFrontiers in pharmacology · 2024Review
- An α-π transition in S6 shapes the conformational cycle of the bacterial sodium channel NavAb.The Journal of general physiology · 2023Article
- Article
- 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
- An open state of a voltage-gated sodium channel involving a π-helix and conserved pore-facing asparagine.Biophysical journal · 2022Article
- Sodium Channels and Local Anesthetics-Old Friends With New Perspectives.Frontiers in pharmacology · 2022Review
- Initiating Coarse-Grained MD Simulations for Membrane-Bound Proteins.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Differences in local anaesthetic and antiepileptic binding in the inactivated state of human sodium channel Nav1.4.Biophysical journal · 2021Article
- Phenylalkylamines in calcium channels: computational analysis of experimental structures.Journal of computer-aided molecular design · 2020Article
- Novel charged sodium and calcium channel inhibitor active against neurogenic inflammation.eLife · 2019Article
- Psychotropic Drugs for the Management of Chronic Pain and Itch.Pharmaceuticals (Basel, Switzerland) · 2019Review
- Structural basis for antiarrhythmic drug interactions with the human cardiac sodium channel.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Dimorphite-DL: an open-source program for enumerating the ionization states of drug-like small molecules.Journal of cheminformatics · 2019Article
- Propofol inhibits prokaryotic voltage-gated NaThe Journal of general physiology · 2018Article
- Non-blocking modulation contributes to sodium channel inhibition by a covalently attached photoreactive riluzole analog.Scientific reports · 2018Article
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3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Voltage-gated sodium channels are essential for carrying electrical signals throughout the body, and mutations in these proteins are responsible for a variety of disorders, including epilepsy and pain syndromes. As such, they are the target of a number of drugs used for reducing pain or combatting arrhythmias and seizures. However, these drugs affect all sodium channel subtypes found in the body. Designing compounds to target select sodium channel subtypes will provide a new therapeutic pathway and would maximize treatment efficacy while minimizing side effects. Here, we examine the binding preferences of nine compounds known to be sodium channel pore blockers in molecular dynamics simulations. We use the approach of replica exchange solute tempering (REST) to gain a more complete understanding of the inhibitors' behavior inside the pore of NavMs, a bacterial sodium channel, and NavPas, a eukaryotic sodium channel. Using these simulations, we are able to show that both charged and neutral compounds partition into the bilayer, but neutral forms more readily cross it. We show that there are two possible binding sites for the compounds: (
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