Molecular Modelling and Screening of Androgen Receptor Ligands to treat Prostate Cancer

Abstract

Adenocarcinoma of prostate gland is the second most frequent cancer and sixth leading cause of mortality in males. The growth, development, and homeostasis of the prostate gland are under the control of androgens. Androgens, dihydrotestosterone (DHT) and testosterone bind with the androgen receptor (AR) and stimulate the growth of the prostate gland. The AR antagonists competitively prevent the binding of androgens with AR. So, they are used in the treatment of prostate cancer. The Aim of the study to identify novel AR antagonist that could antagonize mutant ARs for the treatment of androgen independent prostate cancer. The point mutation in the AR increases the volume of the ligand binding pocket to neutralize the bulky functional groups in the AR antagonist. The bulky functional groups of the AR antagonists affect the conformation of the helix-12 of the AR. The helix-12 was essential for the binding with the co-activators. The helix-12 negative and helix-12 positive ARs were used to select new chemical entities among the pharmacophore matched ligands. This led to the identification of ligands having bulky and#946;-iminoenamine groups. The test ligand ARA3 was bulkier and less flexible than the bicalutamide and has improved potency against mutant ARs. The improved potency against mutant AR had led to the effective control of the AR mediated non-genomic phosphorylation and activation of the AKT. The decrease in the activation of AKT had further prevented the over expression of oncogenes such as c-myc, cyclin d1 and bcl2. Bicalutamide did not significantly decrease the gene expression of oncogenes because of its inability to control the phosphorylation and activation of AKT. This is because the bicalutamide has lesser efficacy against mutant AR expressing cell lines. From the study we conclude that, the different handling of AR mediated non-genomic pathway by ARA3 resulted in the induction of apoptosis.