Abstract

Research on the quantitative structure activity relationship (QSAR) of the 4-fluoropyrrolidine-2-carbonitrile and octahydrocyclopenta[b]pyrrole-2-carbonitrile as Dipeptidyl Peptidase IV (DPP4) inhibitor was performed. The molecular descriptors were calculated and best QSAR model was developed, which satisfied statistical parameters such as correlation coefficient R = 0.912 and leave-one-out validation coefficients q2 = 0.608. The predictive quality of the model was tested against test set compounds with R2pred value of 0.7057. A novel compound (ND1) was designed and its predicted IC50 was predicted, which was lower compared with that of parent compound (S24). Molecular docking and molecular dynamics simulation of 40 ns showed the stability of binding orientation of novel compound, parent compound, and native ligand of DPP4. Prediction of affinity using MM-PBSA method revealed that novel compound has comparable affinity with the parent and natural ligands.

Key words: dipeptidyl peptidase, carbonitril, qsar, docking, molecular dynamic simulation, MM-PBSA