3D-QSAR, molecular docking and molecular dynamics simulations of oxazepane amidoacetonitrile derivatives as novel DPPI inhibitors

Dipeptidyl peptidase I (DPPI) inhibitors have potential use in the treatment of neutrophil inflammatory diseases, such as chronic obstructive pulmonary disease. The three-dimensional quantitative structure-activity relationship (3D-QSAR) model was established in this paper based on the computational biology method for 32 DPPI inhibitor compounds. Good predictability was obtained based on the application of the comparative molecular field analyses (CoMFA q2 = 0.582; r2 = 0.994; rpred2 = 0.661) and the comparative molecular similarity index analyses (CoMSIA q2 = 0.757; r2 = 0.964; rpred2 = 0.518). Contour maps illustrated possible areas affecting activity. Molecular docking results showed the interaction between DPPI inhibitors and protein (PDB: 4CDE). Reliability was demonstrated further by the molecular dynamics simulation. These results can help gain insight into the mechanism of action of DPPI inhibitors and can provide a new direction for future design of more effective DPPI inhibitors.