Combined ligand based pharmacophore modeling, virtual screening methods to identify critical chemical features of novel potential inhibitors for phosphodiesterase-5

The central role of phosphodiesterase-5 (PDE5) is to hydrolyze the cyclic guanidine monophosphate which leads male erectile dysfunction. To inhibit the PDE5 activity, integrated computer-aided drug design technologies were utilized to generate pharmacophore modeling, database screening and docking methodologies. 3D pharmacophore models are generated using HypoGen to identify the critical chemical features of PDE5 inhibitors. Among the top ten generated hypotheses, the first hypothesis (Hypo1) was selected as best one. The best pharmacophore model, Hypo1, characterized by one hydrogen bond acceptor-lipid (HBAL), one hydrophobic (H), two ring aromatic (RA) features, also have high cost difference (111.04), good correlation coefficient (0.94) and low root mean square deviation (1.53). Hypo1 model was cross validated by using Fischer’s randomization method, test and decoy sets. The well validated Hypo1 was used as 3D query to screen NCI database. The screened molecules were sorted by applying rule of five, ADMET properties and molecular docking study to refine the retrieved hits. Finally, 3 molecules were showed good interaction with important amino acids in PDE5 active site. All above said validation analysis strongly suggested that Hypo1 will act as reliable and useful tool to identify new potential leads against PDE5 by screen the large databases and also it predicted 3 compounds in our present study which may act as potent inhibitor of PDE5 and these 3 compounds were chosen for further development. 2011 Taiwan Institute of Chemical Engineers. Published by Elsevier B.V. All rights reserved.