3D-QSAR and docking studies of arylmethylamine-based DPP IV inhibitors

The present work was focused on the study of the three-dimensional (3D) structural requirements for the highly potent bioactivity of dipeptidyl peptidase (DPP) IV's inhibitor. At first, molecular dynamic and mechanic (MD/MM) simulations were performed to research the conformations of the potent DPP IV's inhibitor 5-(aminomethyl)-6-(2,4-dichlorophenyl)-2-(3,5-dimethoxy-phenyl)pyrimidin-4-amine. Using the MD/MM-determined molecular conformers as templates, the 3D quantitative structure activity relationship (QSAR) studies were carried out based on a set of arylmethylamine DPP IV inhibitors with the comparative molecular field analysis (CoMFA) approach. The best 3D-QSAR model was constructed with good statistic values of rcv2 and R2 using PLS analyses (CoMFA: rcv2=0.660, R2=0.953). The generated 3D-QSAR model was proved to be reliable by internal and external validations. Docking studies were further performed to analyze the interaction mode between the highly potent or low potent arylmethylamine derivatives and DPP IV. Our flexible docking results also confirmed the possible bioactive conformation obtained from the 3D-QSAR model, of arylmethylamine-based DPP IV inhibitors. The 3D-QSAR model may provide information of pharmacophoric features for further design and optimization of new scaffold compounds with high inhibitory activity to DPP IV.