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.
