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

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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Identifiers

ORCID for Jonathan Essex: orcid.org/0000-0003-2639-2746

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