3D-QSAR, Molecular Docking and Pharmacokinetic Studies: In-Silico Approach to Search Novel Inhibitors of 5-Alpha Reductase for Treatment of Benign Prostatic Hyperplasia

Aim: This study aims to identify novel steroidal 5-alpha reductase (5AR) inhibitors using computational approaches. Objectives: The objective of this study is to exploit the steroidal nuclei for possible modifications by creating a library of 17-oximino-5-androsten-3-carboxamide derivatives and identify potent 5AR inhibitors based on docking and pharmacokinetic parameters. Background: Benign prostatic hyperplasia (BPH) is a condition of aged men that is characterized by lower urinary tract symptoms. Excessive production of dihydrotestosterone (DHT) from testosterone has been found to play a major role in its pathophysiology. Studies targeting the 5AR enzyme have so far resulted in the development of two clinically approved 5AR inhibitors. Methods: Atom-based three-dimensional-quantitative structure-activity relationship (3D-QSAR) models have been developed using a selected series of steroidal derivatives as 5AR inhibitors to elucidate the structural properties required for 5AR inhibitory activities. Further in128;’silico studies (molecular docking and pharmacokinetic properties like adsorption, distribution, metabolism, and excretion) of 17- oximino-5-androsten-3-carboxamide derivatives have also been carried out to identify the binding orientation and protein-ligand interactions responsible for the exhibited activity and drug like properties. Results: The best 3D-QSAR model was generated using Partial Least Square method with an excellent correlation coefficient (R², training set) of 0.882, standard deviation (SD) of 0.09, and a predicted coefficient (Q², test set) of 0.814. Docking analysis indicated that the designed series of compounds have comparable binding affinity from -8.961 to -8.017 to the protein and suggested that hydrophobic and electrostatic moieties can have a key role in the inhibition mechanism. Conclusion: 3D-QSAR, molecular docking and pharmacokinetic studies indicated that 17-oximino-5- androsten-3-carboxamide derivatives could be studied further to provide a new strategy for the treatment of BPH.