Title:vHTS, 3-D Pharmacophore, QSAR and Molecular Docking Studies for
the Identification of Phyto-derived ATP-Competitive Inhibitors of the
BCR-ABL Kinase Domain
Volume: 19
Issue: 2
Author(s): Damilohun Samuel Metibemu, Oluwatoba Emmanuel Oyeneyin*, Ayorinde Omolara Metibemu, Olawole Yakubu Adeniran and Idowu Olaposi Omotuyi
Affiliation:
- Theoretical and Computational Chemistry Unit, Department of Chemical Sciences, Adekunle Ajasin University, Akungba-Akoko, Ondo State, Nigeria
Keywords:
Virtual high throughput screening, 3-D pharmacophore, D-QSAR, molecular docking, BCR-ABL, chronic myelogenous leukaemia.
Abstract:
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.
