Identification of Isovitexin as a novel CYP17A1 inhibitor through virtual screening and evaluation of its anti-cancer effects in MCF-7 breast cancer cells.

Over 75% of breast cancers are hormone receptor positive and are associated with better prognosis after treatment, when compared to other types of breast cancer. However, discontinuation of treatment due to side effects is common among one-third of the patients, leading to poor outcomes. On long-term treatment, development of resistance to the current therapeutics is common. CYP17A1, a key enzyme in androgen and estrogen synthesis, is associated in the development and progression of breast cancers. Phytochemicals, which are abundant in three traditional medicinal plants, Fenugreek, Ginger, and Basil, generally used in regulating hormonal disorders were screened for potential inhibition of CYP17A1, by molecular docking (Autodock Vina). The binding affinities were compared with standard CYP17A1 inhibitors Abiraterone and Ketoconazole. Docking analysis revealed that Isovitexin (- 9.5 kcal/mol) and Orientin (- 9.4 kcal/mol) showed comparable binding affinities to Abiraterone and Ketoconazole. Molecular Simulations and MM-GBSA were employed to explore the stability of ligand-protein complexes. Isovitexin had stable interactions with the CYP17A1 than Orientin evident from the RMSD, RMSF, Protein-Ligand contacts and MM-GBSA values. In silico ADMET profiles of the phytochemicals and standard breast cancer drugs (Letrozole, Tamoxifen, Paclitaxel, and Docetaxel) were evaluated using Swiss ADME and pkCSM and found to be similar. In in vitro assays, Isovitexin was found to be cytotoxic to MCF-7 cells, causing 46% apoptosis at < 10 nM levels. The study reveals that Isovitexin, with high cytotoxicity, may be effective in the treatment of both ER- and PR-positive (MCF-7) cancers. Overall, the findings have implications for the therapeutic development of hormone receptor-positive breast cancers.