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 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, R = 0.836, Adjusted R = 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.