Insight into structural requirements of ACE inhibitory dipeptides: QSAR and molecular docking studies

The angiotensin I-converting enzyme (ACE) has been found to exhibit inhibitory capability against blood pressure. Recently, several ACE inhibitors with different structures have been reported. In the present work, molecular modeling studies using quantitative structure-activity relationship (QSAR) and molecular docking simulations were carried out. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were firstly used to generate 3D-QSAR models. The results indicate that the best CoMFA model has [Formula: see text] = 0.504, [Formula: see text] = 0.5896, and the best CoMSIA model has [Formula: see text] = 0.525, [Formula: see text] = 0.5666. Furthermore, 2D-QSAR models developed by multiple linear regression/MLR, partial least squares regression/PLSR, and support vector machine regression/SVR methods provide highly significant squared correlation coefficient R_tr² values of 0.8380, 0.8650, and 0.8230, external validated correlation coefficient Q_te² of 0.8279, 0.8223, and 0.7255, respectively. The statistical results show satisfactory goodness-of-fit, robustness, and perfect external predictive performance. Moreover, molecular docking studies were employed to predict the binding mode between dipeptides and ACE receptor. The combination of QSAR studies and molecular docking indicates the requirement of certain physicochemical parameters for better ACE inhibitors.