vHTS, 3-D Pharmacophore, QSAR and Molecular Docking Studies for the Identification of Phyto-derived ATP-Competitive Inhibitors of the BCR-ABL Kinase Domain.

Background: Chronic myelogenous leukaemia (CML) constitutes about 15 % of adult leukaemia and is characterized by the overproduction of immature myeloid cells.

Methods: In this study, a virtual high throughput screening (vHTS) technique was employed to screen a library of phytochemicals of reported plants having anticancer activity. A docking score of -10 kcalmol^-1 was used as the cut-off for the selection of phyto-compounds for pharmacophore-based virtual screening. Statistically robust and thoroughly validated QSAR model (R = 0.914, R² = 0.836, Adjusted R² = 0.764, LOO-CV= 0.6680) was derived for the inhibition of BCR-ABL kinase domain.

Results: The virtual screening, pharmacophore screening, QSAR model and molecular docking techniques applied herein revealed ellagic acid, a polyphenolic compound, as a potential competitive inhibitor of the BCR-ABL kinase domain. Ellagic acid binds to the inactive ABL state and forms similar interactions with key residues within the BCR-ABL Kinase domain as obtained in ponatinib (having inhibitory effects on the ABL thr-315I mutant). It forms hydrogen bond interaction with thr-315 residue (the gatekeeper residue). It is not likely to be prone to the various mutations associated with nilotinib because of its small size.

Conclusion: The procedure of VHTs, Pharmacophore, QSAR, and molecular docking applied in this study could help in detecting more anti-CML compounds.