New leads for DPP IV inhibition: structure-based pharmacophore mapping and virtual screening study.

Dipeptidyl peptidase IV (DPP IV) is an attractive target for the development of new antidiabetic drugs. DPP IV inhibitors improve glycemic control by preventing the rapid inactivation of the incretin hormones; glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide. In the current study, virtual screening, using 2D and 3D filters implemented in a hierarchical cascade, was employed to identify new DPP IV inhibitors. Co-crystallized ligands, with potent DPP IV-inhibitory activities, were utilized to generate structure-based pharmacophore models using DS Visualizer software. The derived pharmacophore maps were validated using in-house built database containing active and inactive DPP IV inhibitors. Subsequently, the optimum validated pharmacophore model was used as a search query against two 3D-databases (NCI and in-house built drug databases). Further hit filtration was carried out employing 2D virtual filters based on Lipinski's rule of 5; number of rotatable bonds and other physicochemical filters. 3D filter using high-throughput molecular docking was also applied. As a result, 5 novel DPP IV inhibitors were discovered as potential lead compounds and later confirmed via in vitro bioassay.