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How point mutations confer resistance in BCR-ABL: a computational study

How point mutations confer resistance in BCR-ABL: a computational study
How point mutations confer resistance in BCR-ABL: a computational study
Imatinib is a first generation BCR-Abl tyrosine kinase inhibitor widely used in the treatment of CML. A significant cause of relapse in patients receiving imatinib therapy can be attributed to the development of point mutations in the BCR-Abl tyrosine kinase and resulting imatinib-resistance. Nilotinib is one of several second generation BCR-Abl tyrosine kinase inhibitors developed to treat imatinib-resistant CML. Nilotinib inhibits the majority of imatinib-resistant mutations, however mutations that are resistant to both imatinib and nilotinib persist in patients. These highly resistant mutations include compound mutants, where multiple mutations occur in the same BCR-Abl molecule. Further understanding regarding how mutations confer resistance and the ability to predict the resistance profile of a given compound mutation would enable drug design initiatives, both in CML and other cancers, to be improved in the future.

In this thesis three major computational approaches; molecular dynamics, ligand docking and MM-GBSA have been applied to investigate the effects of single and compound point mutations in the BCR-Abl kinase domain. Wild-type structures of BCR-Abl were studied initially in order to validate methods and act as a benchmark for comparison against the mutant structures. A total of ten mutant structures of inactive BCR-Abl were studied; five in complex with imatinib and five with nilotinib. Using this approach we were able to rank the single mutant structures according to experimental data and test the protocol on two previously unstudied compound mutations
Clapton, Genevieve
f25ee980-4245-46c0-bc6c-d1a1784e39da
Clapton, Genevieve
f25ee980-4245-46c0-bc6c-d1a1784e39da
Essex, Jonathan
1f409cfe-6ba4-42e2-a0ab-a931826314b5

(2015) How point mutations confer resistance in BCR-ABL: a computational study. University of Southampton, Faculty of Natural and Environmental Sciences, Doctoral Thesis, 291pp.

Record type: Thesis (Doctoral)

Abstract

Imatinib is a first generation BCR-Abl tyrosine kinase inhibitor widely used in the treatment of CML. A significant cause of relapse in patients receiving imatinib therapy can be attributed to the development of point mutations in the BCR-Abl tyrosine kinase and resulting imatinib-resistance. Nilotinib is one of several second generation BCR-Abl tyrosine kinase inhibitors developed to treat imatinib-resistant CML. Nilotinib inhibits the majority of imatinib-resistant mutations, however mutations that are resistant to both imatinib and nilotinib persist in patients. These highly resistant mutations include compound mutants, where multiple mutations occur in the same BCR-Abl molecule. Further understanding regarding how mutations confer resistance and the ability to predict the resistance profile of a given compound mutation would enable drug design initiatives, both in CML and other cancers, to be improved in the future.

In this thesis three major computational approaches; molecular dynamics, ligand docking and MM-GBSA have been applied to investigate the effects of single and compound point mutations in the BCR-Abl kinase domain. Wild-type structures of BCR-Abl were studied initially in order to validate methods and act as a benchmark for comparison against the mutant structures. A total of ten mutant structures of inactive BCR-Abl were studied; five in complex with imatinib and five with nilotinib. Using this approach we were able to rank the single mutant structures according to experimental data and test the protocol on two previously unstudied compound mutations

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More information

Published date: 28 February 2015
Organisations: University of Southampton, Chemistry

Identifiers

Local EPrints ID: 397990
URI: http://eprints.soton.ac.uk/id/eprint/397990
PURE UUID: 83791753-dfab-491f-acac-3bb8616e7756
ORCID for Jonathan Essex: ORCID iD orcid.org/0000-0003-2639-2746

Catalogue record

Date deposited: 15 Jul 2016 12:18
Last modified: 06 Jun 2018 13:07

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Contributors

Author: Genevieve Clapton
Thesis advisor: Jonathan Essex ORCID iD

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