Integrated Computational Design and Experimental Approach for the Discovery of Novel Steroidal 5α-Reductase Inhibitors for Benign Prostatic Hyperplasia

Abstract 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.