Profiling the structural determinants of pyrrolidine derivative as gelatinases (MMP-2 and MMP-9) inhibitors using in silico approaches

Quantitative structure activity relationship (QSAR) studies on pyrrolidine derivatives have been established using CoMFA, CoMSIA, and Hologram QSAR analysis to estimate the values (pIC50) of gelatinase inhibitors. When the CoMFA cross-validation value, Q², was 0.625, the training set coefficient of determination, R² was 0.981. In CoMSIA, Q² was 0.749 and R² was 0.988. In the HQSAR, Q² was 0.84 and R² was 0.946. Visualization of these models was performed by contour maps showing favorable and unfavorable regions for activity, while visualization of HQSAR model was performed by a colored atomic contribution graph. Based on the results obtained of external validation, the CoMSIA model was statistically more significant and robust and was selected as the best model to predict new, more active inhibitors. To study the modes of interactions of the predicted compounds in the active site of MMP-2 and MMP-9, a simulation of molecular docking was realized. A combined study of MD simulations and calculation of free binding energy, were also carried out to validate the results obtained on the best predicted and most active compound in dataset and the compound NNGH as control compound. The results confirm the molecular docking results and indicate that the predicted ligands were stable in the binding site of MMP-2 and MMP-9. [Display omitted] •Different methods were used for QSAR modeling for gelatinases (MMP-2 and MMP-9) inhibitors•New potential gelatinases inhibitors were designed based on the QSAR model with high-predicted activity.•The newly designed compounds have good ADMET properties and drug likeness.•Molecular docking study was used to analyze the interaction between ligand/receptor.•The MD simulation and free binding energy supported the interaction stability of best ligands in the active site.