Investigation of angiotensin-I-converting enzyme (ACE) inhibitory tri-peptides: a combination of 3D-QSAR and molecular docking simulations

Abstract

Angiotensin-I-converting enzyme (ACE) is a key enzyme in the regulation of peripheral blood pressure and electrolyte homeostasis. Therefore, ACE is considered as a promising target for treatment of hypertension. In the present work, in order to investigate the binding interactions between ACE and tri-peptides, three-dimensional quantitative structure-activity relationship (3D-QSAR) models using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods were developed. Three different alignment methods (template ligand-based, docking-based, and common scaffold-based) were employed to construct reliable 3D-QSAR models. Statistical parameters derived from the QSAR models indicated that the template ligand-based CoMFA (R _cv ² = 0.761, R _pred ² = 0.6257) and CoMSIA (R _cv ² = 0.757, R _pred ² = 0.6969) models were better than the other alignment-based models. In addition, molecular docking studies were carried out to predict the binding modes of the peptides to ACE. The peptide-enzyme interactions were consistent with the derived 3D contour maps. Overall, the insights gained from this study would offer theoretical references for understanding the mechanism of action of tri-peptides when binding to ACE and aid in the design of more potent tri-peptides.

Fig. 1. (A) Structure of compound 18 used as a template for template ligand-based alignment; (B) the alignment for ACE from the template ligand-based alignment.

Fig. 2. The correlation plots of the actual versus the predicted pIC₅₀ values using the training set based on the CoMFA and CoMSIA models obtained from the activity for ACE.

Fig. 3. CoMFA StDev × Coeff contour plots for ACE inhibitors in combination of compound 18. (A) The steric contour map, where the green and yellow contours represent 80% and 20% level contributions, respectively. (B) The electrostatic contour map, where the blue and red contours represent 80% and 20% level contributions, respectively.

Fig. 4. CoMSIA StDev × Coeff contour plots for ACE inhibitors in combination of compound 18. (A) The steric contour map, where the green and yellow contours represent 80% and 20% level contributions, respectively. (B) The electrostatic contour map, where the blue and red contours represent 80% and 20% level contributions, respectively. (C) The hydrogen bond donor contour map, where the cyan and purple contours represent 80% and 20% level contributions, respectively. (D) The hydrogen bond acceptor contour map, where the magenta and red contours represent 80% and 20% level contributions, respectively.

Fig. 5. (A) The active site amino acid residues around compound 18. (B) The enlargement for the ligand in the binding site after molecular docking, which is displayed in stick, H-bonds are shown as dotted black lines, and the nonpolar hydrogens were removed for clarity.

Fig. 6. (A) The active site amino acid residues around compound 4. (B) The enlargement for the ligand in the binding site after molecular docking, which is displayed in stick, H-bonds are shown as dotted black lines, and the nonpolar hydrogens were removed for clarity.

Fig. 7. Structural superposition of 3BKK-18 and 3BKK-4. The projection highlights the structure of the active site with compound 18 (green) and 4 (cyan), which are displayed in sticks.

Fig. 8. Structure–activity relationship revealed by QSAR studies for ACE peptides.