Unveiling the potential of novel 5α-reductase inhibitors via ligand based drug design, molecular docking and ADME predictions to manage BPH

Benign prostatic hyperplasia (BPH), a prevalent condition among elderly males characterized by the noncancerous enlargement of the prostate gland is due to the increased stromal and epithelial cell numbers. The enlargement is driven by an active dihydrotestosterone (DHT), synthesized from its prohormone testosterone under the catalytic effect of 5 alpha-reductase Type-II (5-AR2) enzyme. To reduce the increased DHT levels and ultimately to control prostate growth, inhibition of the 5-AR represent an interesting therapeutic target. The 3D crystallography structure 5-AR2, a member of the steroid 5-AR family belonging to the class of oxidoreductase has been resolved recently and opened the door to develop selective novel inhibitors of 5-AR Type-II isoform using molecular modeling techniques. The Force field and Gaussian-field three-dimensional quantitative structure-activity relationship (3D-QSAR) models have been developed using 42 selective 5-AR2 inhibitors belonging to chemical class of steroidal androstene. Partial least squares analysis produced statistically significant model with R2 training = 0.9367, 0.9459 and predictability Q2test = 0.7233, 0.8595. Developed 3D-QSAR model include steric, electrostatic, hydrophobic, and hydrogen bond acceptor and donor field indicators, whereas the potential field contributions indicated the importance of steric feature in governing their biological activity. Protein-ligand interaction pattern analysis revealed that amino acid residues GLU57, ARG114, TYR91 present in the active site of 5-AR2 are crucial for lower energy complexes with good binding affinity. Identified hits were finally adjudged for their druggability by determining in-silico pharmacokinetic parameters. Further, RMSD, binding free energy calculations and post MD analysis demonstrated the enhanced binding affinity with better Delta Gbind value (-79.6 +/- 3.9 kcal/mol) of identified ligand A-10 than the reference molecule finasteride (-69.13 +/- 4.69 kcal/mol). Combined approach of ligand-based and structure-based models have provided an improved understanding of the structural properties of androstene class that may be further used to develop novel 5-AR2 inhibitors to be useful in BPH.