Background: 5α-Reductase (5AR), an NADPH dependent enzyme, is expressed in most of
the prostate epithelial cells. By converting testosterone (T) into more potent androgen dihydrotestosterone
(DHT), it plays an important role in men physiology and represents an efficient therapeutic target
for androgen-dependent diseases. Over the last few years, significant efforts have been made in order to
develop 5AR inhibitors (5ARI) to treat Benign Prostatic Hyperplasia because of excessive production of
Methods: In the present study, 2D and 3D QSAR pharmacophore models have been generated for 5ARI
based on known IC50 values with extensive validations. The four featured 2D pharmacophore based PLS
model correlated the topological interactions (SsOHE-index); semi empirical (Quadrupole2) and physicochemical
descriptors (Mol. Wt, Bromines Count, Chlorines Count) with 5AR inhibitory activity, and
has the highest correlation coefficient (r2 = 0.98, q2 =0.84; F = 57.87, pred r2 = 0.88). Internal and external
validation was carried out using test and proposed set of compounds. The contribution plot of electrostatic
field effects and steric interactions generated by 3D-QSAR showed interesting results in terms
of internal and external predictability. The well-validated 2D PLS, and 3D kNN models were used to
search novel 5AR inhibitors with different chemical scaffold. The compounds were further sorted by
applying ADMET properties and in vitro cytotoxicity studies against prostate cancer cell lines PC-3.
Molecular docking studies have also been employed to investigate the binding interactions and to study
the stability of docked conformation in detail.
Results: Several important hydrophobic and hydrogen bond interactions with 5AR lead to the identification
of active binding sites of 4AT0 protein in the docked complex, which include the gatekeeper residues
ALA 63A (Chain A: ALA63), THR 60 A (Chain A: THR60), and ARG 456 A (Chain A:
ARG456), at the hinge region.
Conclusion: Overall, this study suggests that the proposed compounds have the potential as effective
inhibitors for 5AR.