Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/95747
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dc.contributor.authorVerma, Chandra S.en
dc.contributor.authorPereira, Marianaen
dc.contributor.authorFuentes, Gloriaen
dc.contributor.editorSalsbury Jr., Freddieen
dc.date.accessioned2014-01-03T03:13:13Zen
dc.date.accessioned2019-12-06T19:20:44Z-
dc.date.available2014-01-03T03:13:13Zen
dc.date.available2019-12-06T19:20:44Z-
dc.date.copyright2013en
dc.date.issued2013en
dc.identifier.citationPereira, M., Verma, C. S., & Fuentes, G. (2013). Differences in the binding affinities of ErbB family : heterogeneity in the prediction of resistance mutants. PLoS ONE, 8(10), e77054-.en
dc.identifier.issn1932-6203en
dc.identifier.urihttps://hdl.handle.net/10356/95747-
dc.description.abstractThe pressure exerted by drugs targeted to a protein in any therapy inevitably leads to the emergence of drug resistance. One major mechanism of resistance involves the mutation of key residues in the target protein. Drugs that competitively replace a natural substrate are often made ineffective by mutations that reduce the drug’s affinity relative to that of the natural substrate. Hence atomic level understanding of the mechanisms that underlie this behavior is of utmost importance in efforts to design new drugs that can target such mutant proteins. Methods that can predict these mutations before they appear in clinic would be a major advance in the selection of the appropriate treatment strategy in patients. The present computational approach aims to model this emergence in EGFR and ErbB2 after treatment with the drug lapatinib, by investigating the structural, dynamic and energetic effects on these kinases when bound to the natural substrate ATP and to lapatinib. The study reveals binding modes and subpopulations that are presumably normally cryptic and these have been analyzed extensively here with respect to sites that are predicted to be hotspots for resisting mutations. These positions are compared in the context of currently available data from laboratory-based experiments and mechanistic details, at the atomistic level, of the origin of resistance are developed. The prediction of novel mutations, if validated by their emergence in the clinic, will make these methods as a powerful predictive tool which can be used in the design of new kinase inhibitors.en
dc.language.isoenen
dc.relation.ispartofseriesPLoS ONEen
dc.rights© 2013 The Authors. This paper was published in PLoS ONE and is made available as an electronic reprint (preprint) with permission of the authors. The paper can be found at the following official DOI: [http://dx.doi.org/10.1371/journal.pone.0077054]. One print or electronic copy may be made for personal use only. Systematic or multiple reproduction, distribution to multiple locations via electronic or other means, duplication of any material in this paper for a fee or for commercial purposes, or modification of the content of the paper is prohibited and is subject to penalties under law.en
dc.subjectDRNTU::Science::Biological sciencesen
dc.titleDifferences in the binding affinities of ErbB family : heterogeneity in the prediction of resistance mutantsen
dc.typeJournal Articleen
dc.contributor.schoolSchool of Biological Sciencesen
dc.identifier.doi10.1371/journal.pone.0077054en
dc.description.versionPublished versionen
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