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Identification of Small Molecule Inhibitors of BCR/ABL Tyrosine Kinase through Structure Based Virtual Screening



Identification of Small Molecule Inhibitors of BCR/ABL Tyrosine Kinase through Structure Based Virtual Screening



Blood 100(11): Abstract No 1234, November 16



Over 90% of chronic myelogenous leukemia (CML) and 10% to 25% of adult acute lymphoblastic leukemia (ALL) are associated with a reciprocal translocation between chromosomes 9 and 22 that produces a Bcr-Abl fusion gene. Since transformation by BCR/ABL is absolutely dependent on tyrosine kinase activity, it has been evident that BCR/ABL tyrosine kinase domain could be an attractive target for drug development. Herein, we describe the discovery of novel classes of small molecule inhibitors targeted at the catalytic domains of Abl tyrosine kinase, in which a centrally located "activation loop" is not phosphorylated, by computational 3-D database search. A preliminary DOCK screening against the distinctive inactive conformation of the catalytic domain of BCR/ABL was performed on a smaller 3D database that 202,657 commercially available organic compounds had been built via in-house procedures. 20,000 top compounds with steric complementarity to the binding site was selected for rigorous secondary DOCK screening. The docked complex geometries was used for rescoring by other representively scoring functions. 1000 compounds with a high potential to have high scores by different scoring functions was selected for further diversity analysis. From different structurally diverse clusters, 15 compounds were selected for biological assay based on physico-chemical properties, chemical stability, potential toxicity and potential metabolism. Nine of the 15 showed inhibitory activity against Ph+ human K562 cells with IC50 value ranging from 0.4 to 100 mug/ml. Analysis of the computer-generated binding modes showed that the active compounds interacted nicely with inactive conformation of the activation loop in the down-regulated form of ABL tyrosine kinase. The structural details and the unique binding motif may contribute to the future development of BCR/ABL tyrosine kinase inhibitors.

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