Topics in Anti-Cancer Research

Volume: 3

Indexed in: Book Citation Index, Science (BKCI-S), Chemical Abstracts, BIOSIS Previews, EBSCO, Ulrich's Periodicals Directory.

This is the third volume of the Patent eBook Series entitled Topics in Anti-Cancer Research. This eBook comprises updated reviews on topics relevant to modern cancer research published in the journal ...
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Molecular Dynamic Studies Unveil Potential Mechanisms of Resistance to Imatinib in BCR-ABL Mutants

Pp. 319-341 (23)

Tai-Sung Lee, Steven J. Potts and Maher Albitar

Abstract

Large-scale (~36,000 atoms) and long-time (30ns each) molecular dynamics (MD) simulations on the complex of imatinib and 16 common mutants of the ABL tyrosine kinase domain have been performed to study the imatinib resistance mechanisms at the atomic level. MD simulations show that longtime computational simulations offer insightful information that static models, simple homology modeling methods, or short-time simulations cannot provide for the BCR-ABL imatinib resistance problem. Three possible types of mutational effects from those mutants are found: the direct effect on the contact interaction with imatinib (e.g. P-loop mutations), the effect on the conformation of a remote region contacting with imatinib (e.g. T315I), and the effect on interaction between two regions within the BCR-ABL domain (e.g. H396P). Contrary to current consensus, insights of novel imatinib resistance mechanisms are revealed and our findings suggest that drugs with different binding modes may be necessary to overcome the drug resistance due to T315I and other mutations. These insights are discussed in light of the recent relevant patent literature.

Keywords:

BCR-ABL, BCR-ABL1, E255K, E255V, E286K, G250E, H396P, imatinib resistance, K247N, L248V, MD simulation, M244V, M290L, molecular dynamics simulation, Q252H, T315I, Y253F, Y253H, Y312F.

Affiliation:

Center for Integrative Proteomics Research and Department of Chemistry and Chemical Biology, Rutgers University, 174 Frelinghuysen Rd, Piscataway, NJ 08854-8076, USA.