Structure-based design of human pancreatic amylase inhibitors from natural anthocyanin database for type 2 diabetes

Human Pancreatic Amylase (HPA) is an important target for prevention and treatment of type 2 diabetes. Acarbose is currently an available drug as HPA inhibitor, but its gastrointestinal side-effects cannot be neglected. Thus, developing novel HPA inhibitors with no side-effect is of great importance. Herein, we adopted a structure-based design approach and discovered a potent HPA inhibitor, malvidin 3-O-arabinoside (M3A) from the natural anthocyanin database. We identified M3A as an effective HPA inhibitor through virtual screening, enzyme activity and enzyme kinetic assays. We reported the structure-and-activity relationships as anthocyanidin core and glucosyl group both affected the HPA inhibitory effect of anthocyanins. Molecular dynamics indicated that the mode of HPA inhibition of M3A was binding to the HPA key catalytic residues Arg195 and Asp197 through stable hydrogen bonding. In addition, M3A was found to reduce α-helix fractions and increase β-sheet fractions in CD spectrometry. Further in vivo study showed that M3A significantly ameliorated postprandial blood glucose level. Taken together, our results offer new insights for development of novel HPA inhibitors from natural sources as food supplements for type 2 diabetes.