QSAR studies on Withanolide analogues for Anticancer activity

Withanolides are 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 plant of Indian systems of medicine. Withanolides are basically steroidal lactones (highly oxygenated C-28 phytochemicals) and similar to ginsenosides activity. Some of the withanolides have been reported to possess immunomodulatory, anticancer & other activities. In the present investigation, a quantitative structure activity relationship (QSAR) model have been developed against the MCF7, MCF7/BUS, and SK-Br-3 human solid tumor breast cancer cell lines. Relationship correlation coefficient (r2) and cross validation correlation coefficient (r2CV) of QSAR model were 0.77 and 0.73 for MCF7, 0.91 and 0.85 for MCF7/BUS, 0.93 and 0.90 for SK-Br-3 respectively. Developed QSAR model was also evaluated for prediction accuracy through internal, external and randomization validation methods. QSAR results indicate that for MCF7 cancer cell line, atom count (all atoms), and connectivity index (order 2, standard) descriptors correlate well with the activity. Similarly, for, SK-Br-3 cancer cell line, Connectivity Index (order 0, standard), Dipole Vector X (debye), Molar Refractivity, and Shape Index (basic kappa, order 2) descriptors correlated well with activity. Lastly, for MCF7/BUS cancer cell line chemical 2D descriptors viz., Atom Count (all atoms), Dielectric Energy (kcal/mole), Total Energy (Hartree), and Heat of Formation (kcal/mole) correlate well with the breast cancer activity. Moreover, on the basis of screening for oral bioavailability, in silico ADME and toxicity risk assessment, we concluded that compounds Withn_1, Withn_3, Withn_4 and Withn_8 have higher activity. These results can offer useful references for directing the molecular design of lead compound with improved activity. Method Retrieval of Crystal structures 3D crystal structure of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) protein (PDB