ArticleBiochimica et biophysica acta2011
Computational study of drug binding to the membrane-bound tetrameric M2 peptide bundle from influenza A virus.
Article in Biochimica et biophysica acta, 2011. 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, 42 citations in OpenAlex.
- Molecular biophysics and inhibition mechanism of influenza virus A M2 viroporin by adamantane-based drugs - Challenges in designing antiviral agents.Journal of structural biology: X · 2025Article
- Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Influenza A M2 Inhibitor Binding Understood through Mechanisms of Excess Proton Stabilization and Channel Dynamics.Journal of the American Chemical Society · 2020Article
- Put a cork in it: Plugging the M2 viral ion channel to sink influenza.Antiviral research · 2020Review
- All-atom virus simulations.Current opinion in virology · 2018Review
- Transport-Relevant Protein Conformational Dynamics and Water Dynamics on Multiple Time Scales in an Archetypal Proton Channel: Insights from Solid-State NMR.Journal of the American Chemical Society · 2018Article
- Binding and Proton Blockage by Amantadine Variants of the Influenza M2Journal of medicinal chemistry · 2017Article
- Affinity of Rimantadine Enantiomers against Influenza A/M2 Protein Revisited.ACS medicinal chemistry letters · 2017Article
- Acid activation mechanism of the influenza A M2 proton channel.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Viral channel forming proteins--How to assemble and depolarize lipid membranes in silico.Biochimica et biophysica acta · 2016Review
- Hydrogen-bonded water molecules in the M2 channel of the influenza A virus guide the binding preferences of ammonium-based inhibitors.The journal of physical chemistry. B · 2015Article
- Why bound amantadine fails to inhibit proton conductance according to simulations of the drug-resistant influenza A M2 (S31N).The journal of physical chemistry. B · 2015Article
- Emerging antiviral strategies to interfere with influenza virus entry.Medicinal research reviews · 2014Review
- Activation and proton transport mechanism in influenza A M2 channel.Biophysical journal · 2013Article
- The lipophilic bullet hits the targets: medicinal chemistry of adamantane derivatives.Chemical reviews · 2013Review
- Modeling the membrane environment has implications for membrane protein structure and function: influenza A M2 protein.Protein science : a publication of the Protein Society · 2013Review
- Structural basis for proton conduction and inhibition by the influenza M2 protein.Protein science : a publication of the Protein Society · 2012Review
- GPU/CPU Algorithm for Generalized Born/Solvent-Accessible Surface Area Implicit Solvent Calculations.Journal of chemical theory and computation · 2012Article
- Exploring the size limit of templates for inhibitors of the M2 ion channel of influenza A virus.Journal of medicinal chemistry · 2011Article
- Structural and dynamic mechanisms for the function and inhibition of the M2 proton channel from influenza A virus.Current opinion in structural biology · 2011Review
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Authors and funding
4 authors at 3 institutions in 2 countries.
Funding
Abstract
The M2 protein of influenza A virus performs the crucial function of transporting protons to the interior of virions enclosed in the endosome. Adamantane drugs, amantadine (AMN) and rimantidine (RMN), block the proton conduction in some strains, and have been used for the treatment and prophylaxis of influenza A infections. The structures of the transmembrane (TM) region of M2 that have been solved in micelles using NMR (residues 23-60) (Schnell and Chou, 2008) and by X-ray crystallography (residues 22-46) (Stouffer et al., 2008) suggest different drug binding sites: external and internal for RMN and AMN, respectively. We have used molecular dynamics (MD) simulations to investigate the nature of the binding site and binding mode of adamantane drugs on the membrane-bound tetrameric M2-TM peptide bundles using as initial conformations the low-pH AMN-bound crystal structure, a high-pH model derived from the drug-free crystal structure, and the high-pH NMR structure. The MD simulations indicate that under both low- and high-pH conditions, AMN is stable inside the tetrameric bundle, spanning the region between residues Val27 to Gly34. At low pH the polar group of AMN is oriented toward the His37 gate, while under high-pH conditions its orientation exhibits large fluctuations. The present MD simulations also suggest that AMN and RMN molecules do not show strong affinity to the external binding sites.
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