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1 Molecular Simulation Engineering Laboratory, Department of Chemical Engineering, University of Trieste, Trieste, Italy and 2 Experimental Molecular Pathology, Department of Pathology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy
Requests for reprints: Sabrina Pricl, Molecular Simulation Engineering Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy. Phone: 39-40-5583750; Fax: 39-40-569823. E-mail: sabrina.pricl{at}dicamp.units.it
The early stage of chronic myeloid leukemia is triggered by the tyrosine kinase Bcr-Abl. Imatinib mesylate, a selective inhibitor of Bcr-Abl, has been successful in chronic myeloid leukemia clinical trials, but short-lived remissions are usually observed in blast crisis patients. Sequencing of the BCR-ABL gene in relapsed patients revealed a set of mutants that mediate drug resistance. Previously reported work postulated that the missense T315I mutation both alters the three-dimensional structure of the protein binding site, thus decreasing the protein sensitivity for the drug, and does not feature a fundamental hydrogen bond that is critical for binding with imatinib. These speculations, however, were not supported by investigations at the molecular modeling level. Here, we present the results obtained from the application of molecular dynamics simulations to the study of the interactions between T315I Bcr-Abl and imatinib. For the first time, we show that, with respect to the wild-type system, the absence of the supposedly critical H-bond is not the only cause for the failure of receptor inhibition by imatinib, but also a plethora of other protein/drug interactions are drastically and unfavorably changed in the mutant protein.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 4/ 4/05; revised 5/19/05; accepted 6/14/05.
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