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dc.contributor.authorPrachanronarong, Kristina L.
dc.contributor.authorOzen, Aysegul
dc.contributor.authorThayer, Kelly
dc.contributor.authorYilmaz, L. Safak
dc.contributor.authorZeldovich, Konstantin B.
dc.contributor.authorBolon, Daniel N.
dc.contributor.authorKowalik, Timothy F.
dc.contributor.authorJensen, Jeffrey D.
dc.contributor.authorFinberg, Robert W.
dc.contributor.authorWang, Jennifer P.
dc.contributor.authorYilmaz, Nese Kurt
dc.contributor.authorSchiffer, Celia A.
dc.date2022-08-11T08:10:52.000
dc.date.accessioned2022-08-23T17:23:00Z
dc.date.available2022-08-23T17:23:00Z
dc.date.issued2016-12-13
dc.date.submitted2017-02-17
dc.identifier.citationJ Chem Theory Comput. 2016 Dec 13;12(12):6098-6108. Epub 2016 Nov 17. <a href="https://doi.org/10.1021/acs.jctc.6b00703">Link to article on publisher's site</a>
dc.identifier.issn1549-9618 (Linking)
dc.identifier.doi10.1021/acs.jctc.6b00703
dc.identifier.pmid27951676
dc.identifier.urihttp://hdl.handle.net/20.500.14038/48866
dc.description.abstractNeuraminidase (NA) inhibitors are used for the prevention and treatment of influenza A virus infections. Two subtypes of NA, N1 and N2, predominate in viruses that infect humans, but differential patterns of drug resistance have emerged in each subtype despite highly homologous active sites. To understand the molecular basis for the selection of these drug resistance mutations, structural and dynamic analyses on complexes of N1 and N2 NA with substrates and inhibitors were performed. Comparison of dynamic substrate and inhibitor envelopes and interactions at the active site revealed how differential patterns of drug resistance have emerged for specific drug resistance mutations, at residues I222, S246, and H274 in N1 and E119 in N2. Our results show that the differences in intermolecular interactions, especially van der Waals contacts, of the inhibitors versus substrates at the NA active site effectively explain the selection of resistance mutations in the two subtypes. Avoiding such contacts that render inhibitors vulnerable to resistance by better mimicking the dynamics and intermolecular interactions of substrates can lead to the development of novel inhibitors that avoid drug resistance in both subtypes.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=27951676&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttps://doi.org/10.1021/acs.jctc.6b00703
dc.subjectBiochemistry
dc.subjectMedicinal Chemistry and Pharmaceutics
dc.subjectMedicinal-Pharmaceutical Chemistry
dc.subjectMolecular Biology
dc.subjectStructural Biology
dc.subjectVirus Diseases
dc.titleMolecular Basis for Differential Patterns of Drug Resistance in Influenza N1 and N2 Neuraminidase
dc.typeJournal Article
dc.source.journaltitleJournal of chemical theory and computation
dc.source.volume12
dc.source.issue12
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/schiffer/13
dc.identifier.contextkey9705341
html.description.abstract<p>Neuraminidase (NA) inhibitors are used for the prevention and treatment of influenza A virus infections. Two subtypes of NA, N1 and N2, predominate in viruses that infect humans, but differential patterns of drug resistance have emerged in each subtype despite highly homologous active sites. To understand the molecular basis for the selection of these drug resistance mutations, structural and dynamic analyses on complexes of N1 and N2 NA with substrates and inhibitors were performed. Comparison of dynamic substrate and inhibitor envelopes and interactions at the active site revealed how differential patterns of drug resistance have emerged for specific drug resistance mutations, at residues I222, S246, and H274 in N1 and E119 in N2. Our results show that the differences in intermolecular interactions, especially van der Waals contacts, of the inhibitors versus substrates at the NA active site effectively explain the selection of resistance mutations in the two subtypes. Avoiding such contacts that render inhibitors vulnerable to resistance by better mimicking the dynamics and intermolecular interactions of substrates can lead to the development of novel inhibitors that avoid drug resistance in both subtypes.</p>
dc.identifier.submissionpathschiffer/13
dc.contributor.departmentDepartment of Medicine
dc.contributor.departmentDepartment of Microbiology and Physiological Systems
dc.contributor.departmentProgram in Systems Biology
dc.contributor.departmentProgram in Bioinformatics and Integrative Biology
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.source.pages6098-6108


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