Binding mode of the tyrosine kinase inhibitor bosutinib (SKI-606) to Abl kinase

7049 Background: Bosutinib (SKI-606) is a 4-anilino-3-quinolinecarbonitrile Src/Abl kinase inhibitor. The crystal structure of Abl kinase domain in complex with bosutinib has not yet been determined and the mode of binding of this inhibitor is therefore unknown. Methods: In the present study, we used a molecular docking approach to investigate the following: a) Which Abl conformation(s) bosutinib is more likely to bind? b) Which Abl residues are likely to be involved in bosutinib binding? c) Which imatinib-resistant Abl mutants bosutinib is likely to be active against? A three-dimensional model of bosutinib was generated by Chemsketch (http://www.acdlabs.com). Modelling of the human Abl kinase in its inactive (closed) conformation was performed with the software Modeller, v7.7 (http://salilab.org/modeller) adopting the highly related Mus musculus Abl homologue as a template structure (PDB entry: 1OPJ, 0.175nm resolution). Active (open) Abl conformation is available as PDB entry 1OPL. Flexible docking of b...