Exploration of DPP-IV inhibitors with a novel scaffold by multistep in silico screening.

Dipeptidyl peptidase-IV (DPP-IV), an enzyme that degrades incretins-hormones that promote insulin secretion-is a therapeutic target for type 2 diabetes, with a number of its inhibitors having been launched as therapies for diabetes. Since adverse effects of these inhibitors have recently been reported, the development of novel DPP-IV inhibitors with higher efficacy and safety is required. We, therefore, screened for novel DPP-IV inhibitors using the combination of an in silico drug discovery technique and a DPP-IV assay system. We initially selected seven candidate compounds as DPP-IV inhibitors from a database consisting of four million compounds by a multistep in silico screening procedure combining pharmacophore-based screening, docking calculation and the analysis of three-dimensional quantitative structure-activity relationship. We then measured the inhibitory activity of the selected compounds and identified a hit compound. In addition, we discuss the structure-activity relationship between the binding mode model and inhibitory activity of the hit compound.