Identification of diverse dipeptidyl peptidase IV inhibitors via structure-based virtual screening

Dipeptidyl peptidase IV (DPP4) is an important target for the treatment of type II diabetes mellitus. Inhibition of DPP4 will improve glycemic control in such patients by preventing the rapid breakdown and thereby prolonging the physiological actions of incretin hormones. Known DPP4 inhibitors (including marketed drugs and those drug candidates) appear to share similar structural features: the cyanopyrrolidine moieties, the xanthenes/pyrimidine parts and amino-like linkages. In this study, a multi-step virtual screening strategy including both rigid and flexible docking was employed to search for novel structures with DPP4 inhibition. From SPECS database, consisting of over 190,000 commercially available compounds, 99 virtual hits were picked up and 15 of them were eventually identified to have DPP4 inhibitory activities at 5 ~ 50 μM. Diverse structures of our compounds were out of usual structural categories. Hence a pharmacophore model was built to further explore their common binding features on the enzyme. The results provided a new pathway for the discovery of DPP4 inhibitors and would be helpful for further optimization of DPP4 inhibitors.