Molecular docking, 3D-QSAR and simulation studies for identifying pharmacophoric features of indole derivatives as...

Excess of androgens leads to various diseases such as Poly-Cystic Ovarian Syndrome, Prostate Cancer, Hirsutism, Obesity and Acne. 17β-Hydroxysteroid Dehydrogenase type 5 (17β-HSD5) converts androstenedione into testosterone peripherally, thereby significantly contributing to the development of these diseases. Indole-bearing scaffolds are reported as potential 17β-HSD5 inhibitors for the manifestation of diseases arising due to androgen excess. In the present work, we have extensively performed a combination of molecular docking, Gaussian field-based 3D-QSAR, Pharmacophore mapping and MD-simulation studies (100 ns) to identify the pharmacophoric features of indole-based compounds as potent 17β-HSD5 inhibitors. Molecular simulation studies of the most potent compound in the binding pocket of enzyme revealed that the compound 11 was stable in the binding pocket and showed good binding affinity through interactions with various residues of active site pocket. The Molecular mechanics Generalized Born surface area continuum solvation (MM/GBSA) and Molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations revealed that the compound 11 possessed a free binding energy of -36.36 kcal/mol and -7.00 kcal/mol, respectively, which was better as compared to reference compound Desmethyl indomethacin (DES). The developed pharmacophore will be helpful to design novel indole-based molecules as potent 17β-HSD5 inhibitors for the treatment of various androgenic disorders.Communicated by Ramaswamy H. Sarma.