Derivatives of Benzopyrans are Selective Estrogen Receptor beta Agonists (SERBAs): Molecular Modeling study of Benign Prostatic Hyperplasia

Estrogen receptors play a significant role in the pathogenesis of prostate carcinoma (PCa) by estrogen signaling in normal and abnormal growth of the prostate gland. Estrogens directly target prostate tissue by specific estrogen receptors (ER). The human prostate is equipped with a dual system of ERs that undergoes profound remodeling during prostate cancer development and progression. It was reported that ER-beta may play a significant role in prostate cell differentiation and proliferation and may modulate both the initial phases of prostate carcinogenesis and androgen-independent tumor growth. A virtual screening and molecular docking study was conducted on 3500 benzopyrans for the development of new agonists for ER-beta. Molecular docking approach using Lamarckian Genetic Algorithm was carried out to find out the potent agonists for ER-beta on the basis of calculated ligand-protein pairwise interaction energies. The grid maps representing the protein were calculated using auto grid and grid size was set to 60*60*60 points with grid spacing of 0.375 Ǻ. Docking was carried out with standard docking protocol on the basis of a population size of 150 randomly placed individuals; a maximum number of 2.5 *107 energy evaluations, a mutation rate of 0.02, a crossover rate of 0.80 and an elitism value of 1. Ten independent docking runs were carried out for each ligand and results were clustered according to the 1.0 Ǻ RMSD criteria.

The docking result of the study of 3500 molecules demonstrated that the binding energies were in the range of -1.26 kcal/mol to -8.58 kcal/mol with the minimum binding energy of -8.58 kcal/mol. Three molecules showed promising ADMET properties.

Further in-vitro and in-vivo studies are required on these molecules as the binding mode provided hints for the future design of new inhibitors for ER-beta.