Development of pyrrolidine and isoindoline derivatives as new DPP8 inhibitors using a combination of 3D-QSAR technique, pharmacophore modeling, docking studies, and molecular dynamics simulations

Dipeptidyl peptidase proteins (DPPs) are a family of serine proteases with an active, vital role in multiple pathological conditions, including different types of cancer and autoimmune diseases. DPP inhibitors can induce an inflammatory form of cell death by activating inflammasome sensors and pro-caspase 1. This study used docking calculations and extended molecular dynamics simulations to investigate the interaction patterns for DPP8-inhibitor complex structures. We also implemented a novel procedure to develop new DPP8 inhibitors using pharmacophore and CoMFA models, docking studies, and molecular dynamics simulations. Our results showed the critical role of Glu 275, Glu 276, and Tyr 788 residues in the active site of protein in DPP8-inhibitor interaction. We also provided a platform for comparing the effectiveness of the most important DPP8 inhibitors. Moreover, we introduced a new 1G244 derivative with the highest affinity among all the studied compounds to inhibit DPP8 protein.