Background: 5α-Reductase type II (5αR2) inhibition is a promising strategy for benign prostatic hyperplasia treatment. A computational approach including virtual screening, ligand-based 3D pharmacophore modeling, 2D quantitative structure-activity relationship and molecular docking simulations were adopted to develop novel inhibitors. Results: Hits were first filtered via the validated pharmacophore and 2D quantitative structure-activity relationship models. Docking on the recently determined cocrystallized structure of 5αR2 showed three promising hits. Visual inspection results were compared with finasteride ligand and dihydrotestosterone as reference, to explain the role of binding to Glu57 and Tyr91 for 5αR2 selective inhibition. Conclusion: Alignment between Hit 2 and finasteride in the binding pocket showed similar binding modes. The biological activity prediction showed antitumor and androgen targeting activity of the new hits.
Keywords: 2D QSAR; 3D pharmacophore; 5αR2; BPH; virtual screening.