ArticleJournal of the American Chemical Society2011
Molecular dynamics simulation directed rational design of inhibitors targeting drug-resistant mutants of influenza A virus M2.
Article in Journal of the American Chemical Society, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers.
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Who cites it
76 citing papers in PubMed, 140 citations in OpenAlex.
- Adamantane-based inhibitors of the influenza A M2 proton channel: structure-based design, biological evaluation, and synthetic approaches.RSC medicinal chemistry · 2026Review
- Integrating prior knowledge inference with computational multi-omics analysis to reveal host antiviral networks of natural compounds against influenza A virus.Frontiers in cellular and infection microbiology · 2026Article
- 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
- The interplay of polarizable water and protein in the activation of the M2 channel.Frontiers in pharmacology · 2025Article
- In Silico Screening of 1,3,4-Thiadiazole Derivatives as Inhibitors of Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2).Current issues in molecular biology · 2024Article
- Enthalpic Classification of Water Molecules in Target-Ligand Binding.Journal of chemical information and modeling · 2024Article
- Antiviral Approaches against Influenza Virus.Clinical microbiology reviews · 2023Review
- Implementation of Telescoping Boxes in Adaptive Steered Molecular Dynamics.Journal of chemical theory and computation · 2022Article
- High-Throughput Prediction and Design of Novel Conopeptides for Biomedical Research and Development.Biodesign research · 2022Article
- Rimantadine Binds to and Inhibits the Influenza A M2 Proton Channel without Enantiomeric Specificity.Biochemistry · 2021Article
- Effects of Cholesterol on the Partitioning of a Drug Molecule in Lipid Bilayers.The journal of physical chemistry. B · 2021Article
- From Acid Activation Mechanisms of Proton Conduction to Design of Inhibitors of the M2 Proton Channel of Influenza A Virus.Frontiers in molecular biosciences · 2021Review
- Influenza A M2 Inhibitor Binding Understood through Mechanisms of Excess Proton Stabilization and Channel Dynamics.Journal of the American Chemical Society · 2020Article
- Site-directed M2 proton channel inhibitors enable synergistic combination therapy for rimantadine-resistant pandemic influenza.PLoS pathogens · 2020Article
- Put a cork in it: Plugging the M2 viral ion channel to sink influenza.Antiviral research · 2020Review
- Article
- Discovery of M2 channel blockers targeting the drug-resistant double mutants M2-S31N/L26I and M2-S31N/V27A from the influenza A viruses.European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences · 2020Article
- Article
- Perspectives towards antiviral drug discovery against Ebola virus.Journal of medical virology · 2019Review
- Water in protein hydration and ligand recognition.Journal of molecular recognition : JMR · 2019Review
16 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
Influenza A virus M2 (A/M2) forms a homotetrameric proton selective channel in the viral membrane. It has been the drug target of antiviral drugs such as amantadine and rimantadine. However, most of the current virulent influenza A viruses carry drug-resistant mutations alongside the drug binding site, such as S31N, V27A, and L26F, etc., each of which might be dominant in a given flu season. Among these mutations, the V27A mutation was prevalent among transmissible viruses under drug selection pressure. Until now, V27A has not been successfully targeted by small molecule inhibitors, despite years of extensive medicinal chemistry research efforts and high throughput screening. Guided by molecular dynamics (MD) simulation of drug binding and the influence of drug binding on the dynamics of A/M2 from earlier experimental studies, we designed a series of potent spirane amine inhibitors targeting not only WT, but also both A/M2-27A and L26F mutants with IC(50)s similar to that seen for amantadine's inhibition of the WT channel. The potencies of these inhibitors were further demonstrated in experimental binding and plaque reduction assays. These results demonstrate the power of MD simulations to probe the mechanism of drug binding as well as the ability to guide design of inhibitors of targets that had previously appeared to be undruggable.
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Registered trials
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.