ArticleBiophysical journal2009
Binding hot spots and amantadine orientation in the influenza a virus M2 proton channel.
Article in Biophysical journal, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 37 citations in OpenAlex.
- Expanding FTMap for Fragment-Based Identification of Pharmacophore Regions in Ligand Binding Sites.Journal of chemical information and modeling · 2024Article
- Compounds based on Adamantyl-substituted Amino Acids and Peptides as Potential Antiviral Drugs Acting as Viroporin Inhibitors.Current pharmaceutical design · 2024Review
- FTMove: A Web Server for Detection and Analysis of Cryptic and Allosteric Binding Sites by Mapping Multiple Protein Structures.Journal of molecular biology · 2022Article
- Put a cork in it: Plugging the M2 viral ion channel to sink influenza.Antiviral research · 2020Review
- Why Some Targets Benefit from beyond Rule of Five Drugs.Journal of medicinal chemistry · 2019Article
- Analysis of tractable allosteric sites in G protein-coupled receptors.Scientific reports · 2019Article
- Hot-spot identification on a broad class of proteins and RNA suggest unifying principles of molecular recognition.PloS one · 2017Article
- Focused grid-based resampling for protein docking and mapping.Journal of computational chemistry · 2016Article
- Lessons from Hot Spot Analysis for Fragment-Based Drug Discovery.Trends in pharmacological sciences · 2015Review
- Membrane Protein Structure, Function, and Dynamics: a Perspective from Experiments and Theory.The Journal of membrane biology · 2015Review
- Ligand deconstruction: Why some fragment binding positions are conserved and others are not.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- The FTMap family of web servers for determining and characterizing ligand-binding hot spots of proteins.Nature protocols · 2015Article
- How proteins bind macrocycles.Nature chemical biology · 2014Article
- Comprehensive experimental and computational analysis of binding energy hot spots at the NF-κB essential modulator/IKKβ protein-protein interface.Journal of the American Chemical Society · 2013Article
- Obstructing toxin pathways by targeted pore blockage.Chemical reviews · 2012Review
- Structural basis for proton conduction and inhibition by the influenza M2 protein.Protein science : a publication of the Protein Society · 2012Review
- Relationship between hot spot residues and ligand binding hot spots in protein-protein interfaces.Journal of chemical information and modeling · 2012Article
- Hot spot analysis for driving the development of hits into leads in fragment-based drug discovery.Journal of chemical information and modeling · 2012Article
- Analysis of protein binding sites by computational solvent mapping.Methods in molecular biology (Clifton, N.J.) · 2012Article
- Robust identification of binding hot spots using continuum electrostatics: application to hen egg-white lysozyme.Journal of the American Chemical Society · 2011Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Structures of truncated versions of the influenza A virus M2 proton channel have been determined recently by x-ray crystallography in the open conformation of the channel, and by NMR in the closed state. The structures differ in the position of the bound inhibitors. The x-ray structure shows a single amantadine molecule in the middle of the channel, whereas in the NMR structure four drug molecules bind at the channel's outer surface. To study this controversy we applied computational solvent mapping, a technique developed for the identification of the most druggable binding hot spots of proteins. The method moves molecular probes--small organic molecules containing various functional groups--around the protein surface, finds favorable positions using empirical free energy functions, clusters the conformations, and ranks the clusters on the basis of the average free energy. The results of the mapping show that in both structures the primary hot spot is an internal cavity overlapping the amantadine binding site seen in the x-ray structure. However, both structures also have weaker hot spots at the exterior locations that bind rimantadine in the NMR structure, although these sites are partially due to the favorable interactions with the interfacial region of the lipid bilayer. As confirmed by docking calculations, the open channel binds amantadine at the more favorable internal site, in good agreement with the x-ray structure. In contrast, the NMR structure is based on a peptide/micelle construct that is able to accommodate the small molecular probes used for the mapping, but has a too narrow pore for the rimantadine to access the internal hot spot, and hence the drug can bind only at the exterior sites.
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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.