Journal
FEBS LETTERS
Volume 583, Issue 17, Pages 2899-2906Publisher
WILEY
DOI: 10.1016/j.febslet.2009.07.051
Keywords
c-Kit; c-Abl; Imatinib mesylate; Ellipticine; Docking; Molecular dynamics
Funding
- W.M. Keck Foundation
- Educational Advancement Foundation
- Welch Foundation [BH-0018]
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The conformational flexibility exhibited by protein kinases poses an enormous challenge to the design of cancer therapeutics. Additionally the high degree of structural conservation within the kinase superfamily often leads to inhibitors that exhibit little selectivity and substantial cross reactivity. This work investigates the conformational changes that accompany the binding of Gleevec, or imatinib mesylate, to the tyrosine kinases c-Kit and c-Abl. Our analysis is that this fit is driven, at least in part, by the need to exclude water from solvent-exposed backbone hydrogen bonds. Both experimental and molecular modeling studies of the active state inhibitor of the tyrosine kinase c-Abl indicate that solvent exclusion also plays a role in this system. (C) 2009 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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