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

Abstract

To identify novel steroidal 5-alpha reductase (5AR) inhibitors using computational approaches. 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. Benign prostatic hyperplasia (BPH), is a condition of aged men, that is characterized by lower urinary tract symptoms. Excessive production of dihydrostestosterone (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 clinical approved 5AR inhibitors. 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 In‒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. 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. 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.