3D QSAR models built on structure-based alignments of Abl tyrosine kinase inhibitors

The X-ray crystallographic coordinates of the Abl tyrosine kinase domain in its active, inactive, and Src-like inactive conformations were used as targets to simulate the binding mode of a large series of pyrazolo [3,4-d]pyrimidines (known Abl inhibitors) by means of GOLD software. Receptor-based alignments provided by molecular docking calculations were submitted to a GRID-GOLPE protocol to generate 3D QSAR models. Analysis of the results showed that the models based on the inactive and Src-like inactive conformations had very poor statistical parameters, whereas the sole model based on the active conformation of Abl was characterized by significant internal and external predictive ability. Subsequent analysis of GOLPE PLS pseudo-coefficient contour plots of this model gave us a better understanding of the relationships between structure and affinity, providing suggestions for the next optimization process. On the basis of these results, new compounds were designed according to the hydrophobic and hydrogen bond donor and acceptor contours, and were found to have improved enzymatic and cellular activity with respect to parent compounds. Additional biological assays confirmed the important role of the selected compounds as inhibitors of cell proliferation in leukemia cells. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA.