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

The X-ray crystallog. 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 mol. docking calcns. were submitted to a GRID-GOLPE protocol to generate 3D QSAR models. Anal. 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 anal. of GOLPE PLS pseudo-coeff. 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 compds. were designed according to the hydrophobic and hydrogen bond donor and acceptor contours, and were found to have improved enzymic and cellular activity with respect to parent compds. Addnl. biol. assays confirmed the important role of the selected compds. as inhibitors of cell proliferation in leukemia cells.