{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:25:28Z","timestamp":1787016328283,"version":"build-2736575974"},"reference-count":57,"publisher":"Elsevier BV","issue":"2","license":[{"start":{"date-parts":[[2019,8,1]],"date-time":"2019-08-01T00:00:00Z","timestamp":1564617600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2019,8,1]],"date-time":"2019-08-01T00:00:00Z","timestamp":1564617600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"}],"content-domain":{"domain":["molpharm.aspetjournals.org","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Molecular Pharmacology"],"published-print":{"date-parts":[[2019,8]]},"DOI":"10.1124\/mol.119.116640","type":"journal-article","created":{"date-parts":[[2019,6,7]],"date-time":"2019-06-07T15:49:08Z","timestamp":1559922548000},"page":"148-157","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":18,"title":["The L46P Mutant Confers a Novel Allosteric Mechanism of Resistance Toward the Influenza A Virus M2 S31N Proton Channel Blockers"],"prefix":"10.1016","volume":"96","author":[{"given":"Rami","family":"Musharrafieh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panagiotis I.","family":"Lagarias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunlong","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gene S.","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonios","family":"Kolocouris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1124\/mol.119.116640_bib1","doi-asserted-by":"crossref","first-page":"15075","DOI":"10.1073\/pnas.1007071107","article-title":"Structure and mechanism of proton transport through the transmembrane tetrameric M2 protein bundle of the influenza A virus","volume":"107","author":"Acharya","year":"2010","journal-title":"Proc Natl Acad Sci USA"},{"key":"10.1124\/mol.119.116640_bib2","doi-asserted-by":"crossref","first-page":"10037","DOI":"10.1073\/pnas.181342398","article-title":"Electrostatics of nanosystems: application to microtubules and the ribosome","volume":"98","author":"Baker","year":"2001","journal-title":"Proc Natl Acad Sci USA"},{"key":"10.1124\/mol.119.116640_bib3","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1021\/bi901799k","article-title":"Functional studies and modeling of pore-lining residue mutants of the influenza a virus M2 ion channel","volume":"49","author":"Balannik","year":"2010","journal-title":"Biochemistry"},{"key":"10.1124\/mol.119.116640_bib4","doi-asserted-by":"crossref","first-page":"11872","DOI":"10.1021\/bi9014488","article-title":"Design and pharmacological characterization of inhibitors of amantadine-resistant mutants of the M2 ion channel of influenza A virus","volume":"48","author":"Balannik","year":"2009","journal-title":"Biochemistry"},{"key":"10.1124\/mol.119.116640_bib5","doi-asserted-by":"crossref","first-page":"3257","DOI":"10.1021\/ct300400x","article-title":"Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone \u03c6, \u03c8 and side-chain \u03c7(1) and \u03c7(2) dihedral angles","volume":"8","author":"Best","year":"2012","journal-title":"J Chem Theory Comput"},{"key":"10.1124\/mol.119.116640_bib6","doi-asserted-by":"crossref","unstructured":"Bowers KJS, Chow E, Xu H, Dror RO, Eastwood MP, Gregersen BA, Klepesis JL, Kolossvary I, Moraes MA, Sacerdoti FD, et al. (2006) Molecular dynamics\u2014scalable algorithms for molecular dynamics simulations on commodity clusters, in Proceedings of the 2006 ACM\/IEEE conference on Supercomputing; 2006 Nov 11\u201317; Tampa, FL, pp 84, ACM Press, New York.","DOI":"10.1145\/1188455.1188544"},{"key":"10.1124\/mol.119.116640_bib7","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1073\/pnas.0711500105","article-title":"Amantadine-induced conformational and dynamical changes of the influenza M2 transmembrane proton channel","volume":"105","author":"Cady","year":"2008","journal-title":"Proc Natl Acad Sci USA"},{"key":"10.1124\/mol.119.116640_bib8","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1038\/nature08722","article-title":"Structure of the amantadine binding site of influenza M2 proton channels in lipid bilayers","volume":"463","author":"Cady","year":"2010","journal-title":"Nature"},{"key":"10.1124\/mol.119.116640_bib9","doi-asserted-by":"crossref","first-page":"10059","DOI":"10.1128\/JVI.01184-08","article-title":"The influenza virus M2 protein cytoplasmic tail interacts with the M1 protein and influences virus assembly at the site of virus budding","volume":"82","author":"Chen","year":"2008","journal-title":"J Virol"},{"key":"10.1124\/mol.119.116640_bib10","doi-asserted-by":"crossref","first-page":"10089","DOI":"10.1063\/1.464397","article-title":"Particle mesh Ewald: an Nlog(N) method for Ewald sums in large systems","volume":"98","author":"Darden","year":"1993","journal-title":"J Chem Phys"},{"key":"10.1124\/mol.119.116640_bib11","doi-asserted-by":"crossref","first-page":"8577","DOI":"10.1063\/1.470117","article-title":"A smooth particle mesh Ewald method","volume":"103","author":"Essmann","year":"1995","journal-title":"J Chem Phys"},{"key":"10.1124\/mol.119.116640_bib12","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1021\/ct300899n","article-title":"Free energy calculations reveal the origin of binding preference for aminoadamantane blockers of influenza A\/M2TM pore","volume":"9","author":"Gkeka","year":"2013","journal-title":"J Chem Theory Comput"},{"key":"10.1124\/mol.119.116640_bib13","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1002\/(SICI)1096-987X(199604)17:5\/6<490::AID-JCC1>3.0.CO;2-P","article-title":"Merck molecular force field. 1. Basis, form, scope, parameterization, and performance of MMFF94","volume":"17","author":"Halgren","year":"1996","journal-title":"J Comput Chem"},{"key":"10.1124\/mol.119.116640_bib14","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1002\/jcc.540140114","article-title":"Multigrid solution of the Poisson - Boltzmann equation","volume":"14","author":"Holst","year":"1993","journal-title":"J Comput Chem"},{"key":"10.1124\/mol.119.116640_bib15","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1002\/jcc.540160308","article-title":"Numerical solution of the nonlinear Poisson\u2013Boltzmann equation: developing more robust and efficient methods","volume":"16","author":"Holst","year":"1995","journal-title":"J Comput Chem"},{"key":"10.1124\/mol.119.116640_bib16","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1002\/minf.201100135","article-title":"Free energy calculations by the molecular mechanics Poisson-Boltzmann surface area method","volume":"31","author":"Homeyer","year":"2012","journal-title":"Mol Inform"},{"key":"10.1124\/mol.119.116640_bib17","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1021\/acs.jcim.5b00467","article-title":"Interpreting thermodynamic profiles of aminoadamantane compounds inhibiting the M2 proton channel of influenza A by free energy calculations","volume":"56","author":"Homeyer","year":"2016","journal-title":"J Chem Inf Model"},{"key":"10.1124\/mol.119.116640_bib18","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1126\/science.1191714","article-title":"Mechanisms of proton conduction and gating in influenza M2 proton channels from solid-state NMR","volume":"330","author":"Hu","year":"2010","journal-title":"Science"},{"key":"10.1124\/mol.119.116640_bib19","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1021\/acsmedchemlett.8b00336","article-title":"Structure-property relationship studies of influenza A virus AM2-S31N proton channel blockers","volume":"9","author":"Hu","year":"2018","journal-title":"ACS Med Chem Lett"},{"key":"10.1124\/mol.119.116640_bib20","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD: visual molecular dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J Mol Graph"},{"key":"10.1124\/mol.119.116640_bib21","doi-asserted-by":"crossref","first-page":"6885","DOI":"10.1021\/j100078a035","article-title":"A multiple-time-step molecular dynamics algorithm for macromolecules","volume":"98","author":"Humphreys","year":"1994","journal-title":"J Phys Chem"},{"key":"10.1124\/mol.119.116640_bib22","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1021\/acs.jcim.6b00079","article-title":"Alchemical free energy calculations and isothermal titration calorimetry measurements of aminoadamantanes bound to the closed state of influenza A\/M2TM","volume":"56","author":"Ioannidis","year":"2016","journal-title":"J Chem Inf Model"},{"key":"10.1124\/mol.119.116640_bib23","doi-asserted-by":"crossref","first-page":"10967","DOI":"10.1073\/pnas.0804958105","article-title":"Functional studies indicate amantadine binds to the pore of the influenza A virus M2 proton-selective ion channel","volume":"105","author":"Jing","year":"2008","journal-title":"Proc Natl Acad Sci USA"},{"key":"10.1124\/mol.119.116640_bib24","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1006\/jmbi.1996.0897","article-title":"Development and validation of a genetic algorithm for flexible docking","volume":"267","author":"Jones","year":"1997","journal-title":"J Mol Biol"},{"key":"10.1124\/mol.119.116640_bib25","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1063\/1.445869","article-title":"Comparison of simple potential functions for simulating liquid water","volume":"79","author":"Jorgensen","year":"1983","journal-title":"J Chem Phys"},{"key":"10.1124\/mol.119.116640_bib26","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/S0304-4157(98)00006-9","article-title":"Phases and phase transitions of the phosphatidylcholines [published correction appears in Biochim Biophys Acta (2001) 1513:82]","volume":"1376","author":"Koynova","year":"1998","journal-title":"Biochim Biophys Acta"},{"key":"10.1124\/mol.119.116640_bib27","doi-asserted-by":"crossref","first-page":"5387","DOI":"10.1021\/acs.biochem.6b00727","article-title":"The influenza M2 ectodomain regulates the conformational equilibria of the transmembrane proton channel: insights from solid-state nuclear magnetic resonance","volume":"55","author":"Kwon","year":"2016","journal-title":"Biochemistry"},{"key":"10.1124\/mol.119.116640_bib28","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1021\/acs.jmedchem.6b01852","article-title":"Expeditious lead optimization of isoxazole-containing influenza A virus M2-S31N inhibitors using the Suzuki-Miyaura cross-coupling reaction","volume":"60","author":"Li","year":"2017","journal-title":"J Med Chem"},{"key":"10.1124\/mol.119.116640_bib29","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1529\/biophysj.106.082941","article-title":"Ensemble-based convergence analysis of biomolecular trajectories","volume":"91","author":"Lyman","year":"2006","journal-title":"Biophys J"},{"key":"10.1124\/mol.119.116640_bib30","doi-asserted-by":"crossref","first-page":"2033","DOI":"10.1016\/j.str.2013.08.029","article-title":"Asp44 stabilizes the Trp41 gate of the M2 proton channel of influenza A virus","volume":"21","author":"Ma","year":"2013","journal-title":"Structure"},{"key":"10.1124\/mol.119.116640_bib31","doi-asserted-by":"crossref","first-page":"12283","DOI":"10.1073\/pnas.0905726106","article-title":"Identification of the functional core of the influenza A virus A\/M2 proton-selective ion channel","volume":"106","author":"Ma","year":"2009","journal-title":"Proc Natl Acad Sci USA"},{"key":"10.1124\/mol.119.116640_bib32","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.bbamem.2017.10.026","article-title":"Functional studies reveal the similarities and differences between AM2 and BM2 proton channels from influenza viruses","volume":"1860","author":"Ma","year":"2018","journal-title":"Biochim Biophys Acta Biomembr"},{"key":"10.1124\/mol.119.116640_bib33","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1124\/mol.116.105346","article-title":"Pharmacological characterization of the spectrum of antiviral activity and genetic barrier to drug resistance of M2-S31N channel blockers","volume":"90","author":"Ma","year":"2016","journal-title":"Mol Pharmacol"},{"key":"10.1124\/mol.119.116640_bib34","doi-asserted-by":"crossref","first-page":"4177","DOI":"10.1063\/1.467468","article-title":"Constant pressure molecular dynamics algorithms","volume":"101","author":"Martyna","year":"1994","journal-title":"J Chem Phys"},{"key":"10.1124\/mol.119.116640_bib35","doi-asserted-by":"crossref","first-page":"8178","DOI":"10.1128\/JVI.00627-06","article-title":"Distinct domains of the influenza a virus M2 protein cytoplasmic tail mediate binding to the M1 protein and facilitate infectious virus production","volume":"80","author":"McCown","year":"2006","journal-title":"J Virol"},{"key":"10.1124\/mol.119.116640_bib36","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.antiviral.2018.03.002","article-title":"Profiling the in vitro drug-resistance mechanism of influenza A viruses towards the AM2-S31N proton channel blockers","volume":"153","author":"Musharrafieh","year":"2018","journal-title":"Antiviral Res"},{"key":"10.1124\/mol.119.116640_bib37","doi-asserted-by":"crossref","first-page":"2449","DOI":"10.1128\/JVI.72.3.2449-2455.1998","article-title":"The M2 ectodomain is important for its incorporation into influenza A virions","volume":"72","author":"Park","year":"1998","journal-title":"J Virol"},{"key":"10.1124\/mol.119.116640_bib38","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera--a visualization system for exploratory research and analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J Comput Chem"},{"key":"10.1124\/mol.119.116640_bib39","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/0092-8674(92)90452-I","article-title":"Influenza virus M2 protein has ion channel activity","volume":"69","author":"Pinto","year":"1992","journal-title":"Cell"},{"key":"10.1124\/mol.119.116640_bib40","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1016\/j.cell.2010.08.029","article-title":"Influenza virus M2 protein mediates ESCRT-independent membrane scission","volume":"142","author":"Rossman","year":"2010","journal-title":"Cell"},{"key":"10.1124\/mol.119.116640_bib41","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/0021-9991(77)90098-5","article-title":"Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of N-alkanes","volume":"23","author":"Ryckaert","year":"1977","journal-title":"J Comput Phys"},{"key":"10.1124\/mol.119.116640_bib42","doi-asserted-by":"crossref","first-page":"5957","DOI":"10.1021\/acs.biochem.8b00722","article-title":"Random mutagenesis analysis of the influenza A M2 proton channel reveals novel resistance mutants","volume":"57","author":"Santner","year":"2018","journal-title":"Biochemistry"},{"key":"10.1124\/mol.119.116640_bib43","doi-asserted-by":"crossref","first-page":"5949","DOI":"10.1021\/acs.biochem.8b00721","article-title":"A robust proton flux (pHlux) assay for studying the function and inhibition of the influenza a M2 proton channel","volume":"57","author":"Santner","year":"2018","journal-title":"Biochemistry"},{"key":"10.1124\/mol.119.116640_bib44","doi-asserted-by":"crossref","first-page":"13710","DOI":"10.1021\/ja400146z","article-title":"Influenza virus A M2 protein generates negative Gaussian membrane curvature necessary for budding and scission","volume":"135","author":"Schmidt","year":"2013","journal-title":"J Am Chem Soc"},{"key":"10.1124\/mol.119.116640_bib45","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1126\/science.1191750","article-title":"Insight into the mechanism of the influenza A proton channel from a structure in a lipid bilayer","volume":"330","author":"Sharma","year":"2010","journal-title":"Science"},{"key":"10.1124\/mol.119.116640_bib46","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1038\/nature06528","article-title":"Structural basis for the function and inhibition of an influenza virus proton channel [published correction appears in Nature (2008) 452:380]","volume":"451","author":"Stouffer","year":"2008","journal-title":"Nature"},{"key":"10.1124\/mol.119.116640_bib47","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1128\/JVI.76.3.1391-1399.2002","article-title":"Influenza a virus M2 ion channel activity is essential for efficient replication in tissue culture","volume":"76","author":"Takeda","year":"2002","journal-title":"J Virol"},{"key":"10.1124\/mol.119.116640_bib48","doi-asserted-by":"crossref","first-page":"39880","DOI":"10.1074\/jbc.M206582200","article-title":"The gate of the influenza virus M2 proton channel is formed by a single tryptophan residue","volume":"277","author":"Tang","year":"2002","journal-title":"J Biol Chem"},{"key":"10.1124\/mol.119.116640_bib49","doi-asserted-by":"crossref","first-page":"15219","DOI":"10.1021\/jacs.8b06741","article-title":"Inhibitors of the M2 proton channel engage and disrupt transmembrane networks of hydrogen-bonded waters","volume":"140","author":"Thomaston","year":"2018","journal-title":"J Am Chem Soc"},{"key":"10.1124\/mol.119.116640_bib50","doi-asserted-by":"crossref","first-page":"6504","DOI":"10.1021\/jm050543p","article-title":"Modeling water molecules in protein-ligand docking using GOLD","volume":"48","author":"Verdonk","year":"2005","journal-title":"J Med Chem"},{"key":"10.1124\/mol.119.116640_bib51","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2217\/fvl.15.95","article-title":"M2 as a target to combat influenza drug resistance: what does the evidence say?","volume":"11","author":"Wang","year":"2016","journal-title":"Future Virol"},{"key":"10.1124\/mol.119.116640_bib52","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1002\/bip.22623","article-title":"Recent progress in designing inhibitors that target the drug-resistant M2 proton channels from the influenza A viruses","volume":"104","author":"Wang","year":"2015","journal-title":"Biopolymers"},{"key":"10.1124\/mol.119.116640_bib53","doi-asserted-by":"crossref","first-page":"2804","DOI":"10.1021\/jm301538e","article-title":"Discovery of novel dual inhibitors of the wild-type and the most prevalent drug-resistant mutant, S31N, of the M2 proton channel from influenza A virus","volume":"56","author":"Wang","year":"2013","journal-title":"J Med Chem"},{"key":"10.1124\/mol.119.116640_bib54","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1073\/pnas.1216526110","article-title":"Structure and inhibition of the drug-resistant S31N mutant of the M2 ion channel of influenza A virus","volume":"110","author":"Wang","year":"2013","journal-title":"Proc Natl Acad Sci USA"},{"key":"10.1124\/mol.119.116640_bib55","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1021\/acs.jmedchem.7b01536","article-title":"In vitro pharmacokinetic optimizations of AM2-S31N channel blockers led to the discovery of slow-binding inhibitors with potent antiviral activity against drug-resistant influenza A viruses","volume":"61","author":"Wang","year":"2018","journal-title":"J Med Chem"},{"key":"10.1124\/mol.119.116640_bib56","doi-asserted-by":"crossref","first-page":"17987","DOI":"10.1021\/ja508461m","article-title":"Flipping in the pore: discovery of dual inhibitors that bind in different orientations to the wild-type versus the amantadine-resistant S31N mutant of the influenza A virus M2 proton channel","volume":"136","author":"Wu","year":"2014","journal-title":"J Am Chem Soc"},{"key":"10.1124\/mol.119.116640_bib57","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1002\/pro.2232","article-title":"Modeling the membrane environment has implications for membrane protein structure and function: influenza A M2 protein","volume":"22","author":"Zhou","year":"2013","journal-title":"Protein Sci"}],"container-title":["Molecular Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0026895X24009362?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0026895X24009362?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1124\/mol.119.116640","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T05:30:27Z","timestamp":1739943027000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0026895X24009362"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8]]},"references-count":57,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2019,8]]}},"alternative-id":["S0026895X24009362"],"URL":"https:\/\/doi.org\/10.1124\/mol.119.116640","relation":{},"ISSN":["0026-895X"],"issn-type":[{"value":"0026-895X","type":"print"}],"subject":[],"published":{"date-parts":[[2019,8]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"The L46P Mutant Confers a Novel Allosteric Mechanism of Resistance Toward the Influenza A Virus M2 S31N Proton Channel Blockers","name":"articletitle","label":"Article Title"},{"value":"Molecular Pharmacology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1124\/mol.119.116640","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2019 by The American Society for Pharmacology and Experimental Therapeutics","name":"copyright","label":"Copyright"}]}}