Studies on the molecular recognition between bioactive peptides and angiotensin-converting enzyme.

High blood pressure or hypertension is a condition affecting many individuals and represents a controllable risk factor for cardiovascular diseases such as coronary heart disease and stroke. A non-pharmacological approach to manage these includes the application of food components with antihypertensive activity. Milk protein-derived peptides have been exploited as natural hypotensive agents, namely the peptides Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP), already commercialized in functional foods as a potential alternative to synthetic drugs. These bioactive peptides inhibit in vitro and in vivo the Angiotensin I-converting enzyme (ACE), a protein with an important role in blood pressure regulation. In this work, we attempted to elucidate the possible mode of interaction between the peptides and ACE, including mechanisms of binding to the cofactor Zn2+, and further contrast this with the known mode of inhibition exerted by synthetic drugs (Captopril, Enalaprilat and Lisinopril). The bioactive peptide Ala-Leu-Pro-Met-His-Ile-Arg (ALPMHIR), also known to inhibit the enzyme ACE but with a lower efficiency than VPP and IPP, was utilized in the docking studies for comparison. It was observed that the best docking poses obtained for VPP and IPP were located at the ACE catalytic site with very high resemblance to the drugs mode of interaction, including the coordination with Zn2+. As for ALPMHIR, the best docking poses were located in the narrow ACE channel outside the catalytic site, representing higher affinity energies and fewer resemblances with the interaction established by drugs. Copyright (c) 2008 John Wiley & Sons, Ltd.