Identification of Potential Cytochrome p450c 17 Alpha Inhibitors for the Treatment of PCOS via Scaffold Hopping and Fragment-Based De-Novo Drug Design

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting reproductive-aged women. It is characterized by hyperandrogenism, ovarian dysfunction, and metabolic abnormalities. Current treatment options have limitations and many women remain undiagnosed or untreated. Cytochrome P450c 17 alpha (CYP17A1) plays a key role in androgen biosynthesis and is a potential therapeutic target for PCOS. Known CYP17A1 inhibitors metformin, spironolactone, and clomiphene were used for scaffold hopping to generate structurally diverse compounds. These were screened against CYP17A1 (PDB code 3RUK) through molecular docking. Hits were subjected to fragment-based de novo design and further docking. Quality parameters, ADMET profiling, and biological activity predictions were evaluated. Scaffold hopping yielded 300 compounds, from which 10 hits were identified. De novo design generated 326 ligands, of which 7 demonstrated superior binding to 3RUK compared to reference drugs. These hits formed favourable interactions within the binding pocket and exhibited drug-like properties. They were predicted to inhibit CYP17A1 and show activity for PCOS-related indications. Toxicity profiling suggested an acceptable safety profile. Through an integrated in silico workflow, this study identified 7 novel CYP17A1 inhibitor scaffolds as potential leads for PCOS treatment. Their predicted bioactivities and properties warrant further experimental validation. This approach provides a foundation for the development of improved PCOS therapeutics targeting androgen biosynthesis.