QSAR Analysis And Virtual Screening Of Steroidal Androgen Receptor Antagonist

According to the latest World Cancer Report 2014,prostate cancer?PCa?has become the second most common cancer among men in the world.The morbidity rate of PCa has reached 15%,which is merely 1.7% lower than the leading lung cancer.It is reported that about 1100,000 people diagnosed as new PCa patients in 2012.Additionally researchers pointed out that prostate cancer is not the privilege of men,women have similar prostate tissue,which also has the risk of cancer.The androgen receptor?AR?,a ligand inducible transcription factor in the nuclear hormone receptor super family,plays a critical role in the development and progress of PCa.Natural hormone testosterone?T?and dihydrotestosterone?DHT?,known as androgens,are the endogenous ligands of AR.When bound to AR,androgens play significant roles in the sexual development,function and musculoskeletal growth of male.The main mechanism of androgen action is to regulate the gene expression by mean of binding to AR,changing the level of specific proteins in cells,and controlling cell behavior.Therefore,a rational approach to cure PCa is the use of antiandrogens to prevent the interaction of T or DHT with AR.At present,androgen receptor antagonists,such as bicalutamide and flutamide,are used as main hormone therapies for prostate cancer.Although these antiandrogens exhibit good efficacy in many cases and comprise an important part of effective therapeutics the emergence of recurrent and metastatic forms of castration-resistant PCa?CRPC?becomes a major challenge,with a median survival of only 1² year.A possible reason is that these antiandrogens have partial agonistic activities at high concentration in vitro.Therefore,the discovery of new R antagonists with high antiandrogen activities is highly expected.Androgen receptor antagonists can be divided into two categories according to the structure: steroids and non-steroidal.Here in this study,to aid the research and development of steroidal antiandrogens,we investigate the relationships between a series of 7?-substituted dihydrotestosterone derivatives and corresponding antiandrogen activities.The vital features related to the bioactivities is explored,and a linear multiple linear regression?MLR?model is established according to OECD principles,using the QSARINS program.Then the MLR model,thoroughly and strictly validated by various internal and external validation techniques,is used to virtually screen new dihydrotestosterones,without experimental bioactivities,downloaded from PubChem database.Results in the finding of novel compounds CID₇0128824?CID₇0127147 and CID₇0126881,whose in silico bioactivities are much higher than the published best one,even higher than bicalutamide.Besides,molecular docking is used to study the possible binding mode of compounds owning high in silico activities with androgen receptor.Through the analysis of the binding free energy and residue energy decomposition,we concluded that the newly discovered chemicals can in silico bind to AR with similar position and mechanism to the reported active compound and the van der Waals interaction is the main driving the binding process.