Differences in the binding affinities of ErbB family : heterogeneity in the prediction of resistance mutants
The 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 m...
| Main Authors: | , , |
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| Format: | Journal Article |
| Language: | English |
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2014
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| Online Access: | https://hdl.handle.net/10356/95747 http://hdl.handle.net/10220/18380 |
| _version_ | 1811684627861995520 |
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| author | Verma, Chandra S. Pereira, Mariana Fuentes, Gloria |
| author2 | Salsbury Jr., Freddie |
| author_facet | Salsbury Jr., Freddie Verma, Chandra S. Pereira, Mariana Fuentes, Gloria |
| author_sort | Verma, Chandra S. |
| collection | NTU |
| description | The 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. |
| first_indexed | 2024-10-01T04:31:39Z |
| format | Journal Article |
| id | ntu-10356/95747 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T04:31:39Z |
| publishDate | 2014 |
| record_format | dspace |
| spelling | ntu-10356/957472023-02-28T17:04:05Z Differences in the binding affinities of ErbB family : heterogeneity in the prediction of resistance mutants Verma, Chandra S. Pereira, Mariana Fuentes, Gloria Salsbury Jr., Freddie School of Biological Sciences DRNTU::Science::Biological sciences The 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. Published version 2014-01-03T03:13:13Z 2019-12-06T19:20:44Z 2014-01-03T03:13:13Z 2019-12-06T19:20:44Z 2013 2013 Journal Article Pereira, 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-. 1932-6203 https://hdl.handle.net/10356/95747 http://hdl.handle.net/10220/18380 10.1371/journal.pone.0077054 24194858 en PLoS ONE © 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. application/pdf |
| spellingShingle | DRNTU::Science::Biological sciences Verma, Chandra S. Pereira, Mariana Fuentes, Gloria Differences in the binding affinities of ErbB family : heterogeneity in the prediction of resistance mutants |
| title | Differences in the binding affinities of ErbB family : heterogeneity in the prediction of resistance mutants |
| title_full | Differences in the binding affinities of ErbB family : heterogeneity in the prediction of resistance mutants |
| title_fullStr | Differences in the binding affinities of ErbB family : heterogeneity in the prediction of resistance mutants |
| title_full_unstemmed | Differences in the binding affinities of ErbB family : heterogeneity in the prediction of resistance mutants |
| title_short | Differences in the binding affinities of ErbB family : heterogeneity in the prediction of resistance mutants |
| title_sort | differences in the binding affinities of erbb family heterogeneity in the prediction of resistance mutants |
| topic | DRNTU::Science::Biological sciences |
| url | https://hdl.handle.net/10356/95747 http://hdl.handle.net/10220/18380 |
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