Abstract
Withaferin-A (Wi-A), a secondary metabolite extracted from Ashwagandha (Withania somnifera), has been shown to possess anticancer activity. However, the molecular mechanism of its action and the signaling pathways have not yet been fully explored. We performed an inverse virtual screening to investigate its binding potential to the catalytic site of protein kinases and identified ABL as a strong candidate. Molecular docking and molecular dynamics simulations were undertaken to investigate the effects on BCR-ABL oncogenic signaling that is constitutively activated yielding uncontrolled proliferation and inhibition of apoptosis in Chronic Myeloid Leukemia (CML). We found that Wi-A and its closely related withanolide, Withanone (Wi-N), interact at both catalytic and allosteric sites of the ABL. The calculated binding energies were higher in the case of Wi-A at catalytic site (−82.19 ± 5.48) and allosteric site (−67.00 ± 4.96) as compared to the clinically used drugs Imatinib (−78.11 ± 5.21) and Asciminib (−54.00 ± 6.45) respectively. Wi-N had a lesser binding energy (−42.11 ± 10.57) compared to Asciminib at the allosteric site. The interaction and conformational changes, subjected to ligand interaction, were found to be similar to the drugs Imatinib and Asciminib. The data suggested that Ashwagandha extracts containing withanolides, Wi-A and Wi-N may serve as natural drugs for the treatment of CML. Inhibition of ABL is suggested as one of the contributing factors of anti-cancer activity of Wi-A and Wi-N, warranting further in vitro and in vivo experiments.
Highlights
Cancer is most consistently defined by uncontrolled division of cells yielding their abnormal mass at any local site in the body or even spread to distant organs through the blood or lymphatic stream by a process called metastasis [1]
Imatinib and Asciminib were used as controls for ABL
Considering the role of constitutively activated kinases in oncogenic signaling, and anticancer activity of Wi-A demonstrated in previous studies, we anticipated that it may inhibit kinases and performed inverse virtual screening using the catalytic site of protein kinases
Summary
Cancer is most consistently defined by uncontrolled division of cells yielding their abnormal mass at any local site in the body or even spread to distant organs through the blood or lymphatic stream by a process called metastasis [1]. Chronic myelogenous leukemia (CML) is a type of cancer in which the bone marrow produces an excess of white blood cells of myelogenous origin. Accounting for about 15% of all cases of leukemia, CML is clinically categorized as chronic, accelerated and blastic, with 20% blast cells in the blood/ bone marrow, respectively [2]. Since the cancerous cells in CML are disposed directly into the bloodstream, such a disease has a higher incidence of multiple organ involvement and is often associated with poor prognosis.
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