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Nevertheless, we have discovered small-molecule drugs that inhibit S31N with potencies greater than amantadine\u2019s potency against WT M2. Drug binding locks the protein into a well-defined conformation, and the NMR structure of the complex shows the drug bound in the homotetrameric channel, threaded between the side chains of Asn31. Unrestrained molecular dynamics simulations predicted the same binding site. This S31N inhibitor, like other potent M2 inhibitors, contains a charged ammonium group. The ammonium binds as a hydrate to one of three sites aligned along the central cavity that appear to be hotspots for inhibition. These sites might stabilize hydronium-like species formed as protons diffuse through the outer channel to the proton-shuttling residue His37 near the cytoplasmic end of the channel.<\/jats:p>","DOI":"10.1073\/pnas.1216526110","type":"journal-article","created":{"date-parts":[[2013,1,10]],"date-time":"2013-01-10T09:33:29Z","timestamp":1357810409000},"page":"1315-1320","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":223,"title":["Structure and inhibition of the drug-resistant S31N mutant of the M2 ion channel of influenza A virus"],"prefix":"10.1073","volume":"110","author":[{"given":"Jun","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158-9001;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yibing","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158-9001;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunlong","family":"Ma","sequence":"additional","affiliation":[{"name":"Departments of bMolecular Biosciences and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacomo","family":"Fiorin","sequence":"additional","affiliation":[{"name":"Institute for Computational Molecular Science and Department of Chemistry, Temple University, Philadelphia, PA 19122-6078; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jizhou","family":"Wang","sequence":"additional","affiliation":[{"name":"Influmedix, Inc., Radnor, PA 19087-5221"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence H.","family":"Pinto","sequence":"additional","affiliation":[{"name":"Neurobiology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Lamb","sequence":"additional","affiliation":[{"name":"Departments of bMolecular Biosciences and"},{"name":"Howard Hughes Medical Institute, Northwestern University, Evanston, IL 60208-3500;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael L.","family":"Klein","sequence":"additional","affiliation":[{"name":"Institute for Computational Molecular Science and Department of Chemistry, Temple University, Philadelphia, PA 19122-6078; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William F.","family":"DeGrado","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158-9001;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2013,1,9]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1038\/nrd2175","article-title":"Antiviral agents active against influenza A viruses","volume":"5","author":"De Clercq E","year":"2006","unstructured":"E De Clercq, Antiviral agents active against influenza A viruses. 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