Molecular docking, QSAR and ADMET studies of withanolide analogs against breast cancer.

Withanolides are a group of pharmacologically active compounds present in most prodigal amounts in roots and leaves of Withania somnifera (Indian ginseng), one of the most important medicinal plants of Indian traditional practice of medicine. Withanolides are steroidal lactones (highly oxygenated C-28 phytochemicals) and have been reported to exhibit immunomodulatory, anticancer and other activities. In the present study, a quantitative structure activity relationship (QSAR) model was developed by a forward stepwise multiple linear regression method to predict the activity of withanolide analogs against human breast cancer. The most effective QSAR model for anticancer activity against the SK-Br-3 cell showed the best correlation with activity (r2=0.93 and rCV2 =0.90). Similarly, cross-validation regression coefficient (rCV2=0.85) of the best QSAR model against the MCF7/BUS cells showed a high correlation (r2=0.91). In particular, compounds CID_73621, CID_435144, CID_301751 and CID_3372729 have a marked antiproliferative activity against the MCF7/BUS cells, while 2,3-dihydrowithaferin A-3-beta-O-sulfate, withanolide 5, withanolide A, withaferin A, CID_10413139, CID_11294368, CID_53477765, CID_135887, CID_301751 and CID_3372729 have a high activity against the Sk-Br-3 cells compared to standard drugs 5-fluorouracil (5-FU) and camptothecin. Molecular docking was performed to study the binding conformations and different bonding behaviors, in order to reveal the plausible mechanism of action behind higher accumulation of active withanolide analogs with β-tubulin. The results of the present study may help in the designing of lead compound with improved activity.