Molecular insights into the interaction of angiotensin I-converting enzyme (ACE) inhibitors and HEXXH motif

Nutraceuticals and functional foods garner a lot of attention as potential alternative therapies for treatment of (pre)hypertension. Food-derived proteins release large variety of bioactive peptides which are similar in structure to peptide sequences acting in the organism and therefore can modulate their physiological functions. Val-Pro-Pro (VPP) is a milk-derived tripeptide with assumed mild inhibitory activity against angiotensin-converting enzyme (ACE). Computational (DFT) methods are applied on simplified models of Zn²⁺-HEXXH binding motif without/with bound inhibitors in order to assess the ability of two pharmaceutical drugs (Captopril and Lisinopril) and Val-Pro-Pro to coordinate with Zn²⁺-HEXXH binding motif of ACE. Both drugs have significant affinity towards the active site, while the Val-Pro-Pro tripeptide has weaker affinity. The obtained results shed light on the thermodynamic aspects of the inhibitors coordination to the Zn²⁺-HEXXH binding motif of ACE.