In silico Identification of potential 5α‒reductase inhibitors for prostatic diseases: QSAR modelling, molecular docking, and pre ADME predictions

Abstract

Steroids assume an essential part in a several processes, ranging from the differentiation, growth, development, physiological and regenerative functions in the human body,1 because of their ability to cross membrane easily.2 Steroids as well as their derivatives have the potential to be developed as drugs for the treatment of a large number of diseases including cardiovascular, autoimmune diseases, brain tumours, breast cancer, osteoarthritis, prostate cancer etc.3‒6 The promise of using steroids for development of lead molecules lies in the regulation of a variety of biological processes by these molecules and being a fundamental class of signalling molecules.7,8 Benign prostatic hyperplasia (BPH) and Prostate Cancer (PC), are the leading disorders of the old age men. These prostatic diseases are characterized by a progressive enlargement of prostatic tissue, that results in the obstruction of proximal urethra and cause urinary flow disturbances.9 Nearly half of men aged over 50years show histological evidence of BPH and PC and proportion increases to 80% by the age of 70.10 Dihyrotestesterone (DHT) hypothesis postulates that androgens play an important role in growth of prostate. Male hormone testosterone (T), is biosynthesized in testicles and adrenal glands, and converted to more potent androgen i.e. dihydrotestosterone (DHT) by NADPH dependent enzyme 5α‒Reductase (5AR). 5AR is a membrane‒ bound enzyme that irreversibly catalyses the reduction of 4‒ene‒3‒ oxosteroids to the corresponding 5α‒3‒oxosteroids Figure 1. Three isozymes have been identified for 5AR based on their gene sequence, location, and pH. Type 1 isozyme (5AR1) is expressed in skin and liver and show maximal activity at pH ranging from 6.0∼8.5, whereas type 2 isozyme (5AR2) shows its activity at pH 5.5 in prostate and other genital tissues.11 Recently, type 3 isozyme (5AR3) has also been identified in castration‒resistant prostate cancer cells including other tissues like pancreas, brain, skin and adipose tissues.12‒14 5AR has emerged as a therapeutic target, as 5α‒Reductase Inhibitors (5ARIs) by causing the suppression of DHT biosynthesis provided a logical treatment for BPH and PC.15,16 Further, isolation and characterisation of the three different isozymes have led in the advancement of new and selective inhibitors with improved anticancer therapies.17 Computer Aided Drug Designing (CADD) in perspective of QSAR between natural activity and physicochemical descriptor, is a gadget that has been utilized to build the productivity of the medication disclosure process.18 Though primary sequence of 5AR isozymes, are available, but crystal structure of 5AR have yet not been determined as yet they have not been isolated and purified from tissues or cells despite. In the absence of structural information of target protein, different receptor mapping techniques can create permitting developing 3D surrogate of the coupling pocket and could be utilized to predict