期刊
MOLECULAR ONCOLOGY
卷 7, 期 5, 页码 968-975出版社
WILEY
DOI: 10.1016/j.molonc.2013.06.001
关键词
BCR-ABL; Dasatinib; Binding mode; Hydrophobic-spine; Resistance
类别
资金
- European Commission DG Research in the 7th Framework Program [228398]
Dasatinib is a second-generation BCR-ABL inhibitor approved for the treatment of patients with chronic myeloid leukemia, both in the frontline and in the imatinib-resistant/ intolerant settings. The high affinity of dasatinib for the protein is currently assumed to result from its ability to bind both the active and inactive conformations of the BCR-ABL kinase. In the present work, using state of the art molecular simulation techniques we prove that dasatinib exhibits a highly selective preference for the active (open) BCR-ABL conformation. By using three different BCR-ABL conformations (active, inactive, and intermediate inactive) we show that, from a thermodynamic standpoint, the affinity of dasatinib for BCR-ABL drastically decreases in the order: active > alternative inactive > inactive, as a result of differential contributions from the single residues lining the kinase binding pocket and the concomitant stabilization/destabilization of the kinase hydrophobic spine. Molecule-pulling experiments also corroborate this trend as significantly lower forces and smaller times are required to extract dasatinib from its inactive BCR-ABL complexes with respect to the active complex counterparts. Importantly, our results support recent NMR solution results demonstrating no evidence of dasatinib bound to the inactive form of BCR-ABL. (C) 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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