Texas Southern University Houston, Texas, United States
Purpose: Prostate cancer (PC) is a proliferative disorder characterized by abnormal cell growth that originates in the prostate gland. An effective way of treating PC is androgen deprivation therapy (ADT). However, at an advance stage, PC stops to respond to ADT, and this is referred to as castrate-resistant prostate cancer (CRPC). Earlier research reported GMC1 effectively inhibit androgen receptor (AR) and glucocorticoid receptor (GR) activities in a variety of PC lines. However, poor solubility of GMC1 in water and lipid has made it desirable and necessary to design and develop new pharmacophores/analogues with suitable water solubility, liquid stability, and therapeutically potent against PC. Methods: This study is aimed at designing and developing new analogues of GMC1, and this study employed both computational and in vitro methods to identified compounds with inhibitory potentials against CRPC related proteins and PC cells. SWISS-similarity and Zinc databases were utilized for screening of compounds to identify GMC1-structurally related compounds with better physicochemical properties. In vitro inhibitory activity against MDA cells was done using luciferase induction assay. Results: A search of the databases identified over 7000 analogues of GMC1. Out of the over 7000 GMC1 analogues, 231 were predicted to show better solubility in lipid and water than GMC1. And the results of the molecular docking analysis revealed 27 compounds exhibited higher docking scores toward the FK1 domain of FKBP52 protein compared to the reference drug, FK506 and GMC1. For the AR and GR, 35 and 40 analogues respectively exhibited higher docking scores towards their ligand binding domain (LBD) than the reference drugs and GMC1. A further molecular dynamic simulations study of the best docked compounds showed 8, 4 and 7 compounds showed better binding affinities and stable conformation at the binding sites of GR, FKBP52 and AR, respectively. In vitro evaluation of the EC50 of the identified compounds (25 µM) using luciferase induction assay against AR and GR revealed two compounds, RJ3 and RJ11 showed 45 and 90 % inhibition, respectively. However, toxicity assay showed the two compounds lowers reporter’s expression. Conclusion: The study showed the two identified compounds ti be promising therapeutic agent, however, more assays regarding their toxicity are required
