Integrated Computational Design and Experimental Approach for the Discovery of Novel Steroidal 5α-Reductase...

Advancements in computational drug design have enabled rapid identification of lead molecules with improved precision and reduced experimental attrition. In this study, an integrated in silico-in vitro approach was employed to design steroidal inhibitors targeting 5α-reductase type 2 (5-AR2), a key enzyme involved in benign prostatic hyperplasia (BPH). A ligand-based pharmacophore model (ADHHHR_1), developed from known inhibitors, guided the design of androstane derivatives. Subsequent 3D-QSAR and molecular docking against 5-AR2 (PDB ID: 7BW1) identified NDPR-2 and NDPR-5 as promising candidates with favorable binding interactions. Molecular dynamics simulation analysis supported the stability of ligand-protein complexes. In silico ADME predictions indicated good drug likeness and oral bioavailability. In vitro studies demonstrated low cytotoxicity in LNCaP cells and measurable inhibitory activity against 5-AR. Overall, NDPR-2 and NDPR-5 emerged as promising lead candidates for further optimization toward safer and more effective BPH therapeutics.