Integrated in silico-in vitro molecular modeling and design of halogenated phenylalanine-containing antihypertensive peptide inhibitors with halogen bonds to target human angiotensin-I-converting enzyme

Abstract

Angiotensin-I-converting enzyme (ACE) is a key regulator of blood pressure as its critical role in the renin-angiotensin-aldosterone and kallikrein-kinin systems. Although a variety of natural and food peptides have been discovered to possess ACE-inhibitory activity over the past decades, they cannot be directly used as drugs due to their low efficiency and bad bioavailability. In this study, the intermolecular interaction of ACE with a snake venom inhibitor of bradykinin potentiating peptide b (BPPb) was investigated systematically at structural and energetic levels. The C-terminal region of the peptide can tightly pack against the enzyme active site and is primarily responsible for the enzyme inhibition. A tetrapeptide that covers the C-terminal region of BPPb exhibited a satisfactory ACE-inhibitory profile, which was used as start to generate a number of phenylalanine (Phe)-containing antihypertensive peptide inhibitors. The ortho-, meta- and para-positions of peptide Phe−2 phenyl moiety were systematically substituted with halogen atoms. It is revealed that bromine substitution separately at the meta- and para-positions can considerably improve the peptide inhibitory activity by 7.6-fold and 3.7-fold by forming a bifurcated halogen-bonding system with ACE His513 and Val518 residues as well as a binary halogen-bonding system with ACE Glu384 residue, respectively.