vHTS, 3-D Pharmacophore, QSAR and Molecular Docking Studies for the Identification of Phyto-derived ATP-Competitive Inhibitors of the BCR-ABL Kinase Domain.
| Autor: | Metibemu DS; Department of Biochemistry, Adekunle Ajasin University, Akungba-Akoko, Ondo State, Nigeria., Oyeneyin OE; Theoretical and Computational Chemistry Unit, Department of Chemical Sciences, Adekunle Ajasin University, Akungba-Akoko, Ondo State, Nigeria., Metibemu AO; Department of Biochemistry, Adekunle Ajasin University, Akungba-Akoko, Ondo State, Nigeria., Adeniran OY; Department of Biochemistry, Adekunle Ajasin University, Akungba-Akoko, Ondo State, Nigeria., Omotuyi IO; Department of Biochemistry, Adekunle Ajasin University, Akungba-Akoko, Ondo State, Nigeria. |
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| Jazyk: | angličtina |
| Zdroj: | Current drug discovery technologies [Curr Drug Discov Technol] 2022; Vol. 19 (2), pp. e021221198480. |
| DOI: | 10.2174/1570163819666211202092632 |
| Abstrakt: | 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, R 2 = 0.836, Adjusted R 2 = 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. (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.) |
| Databáze: | MEDLINE |
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