Structure-based design and optimization of antihypertensive peptides to obtain high inhibitory potency against both renin and angiotensin I-converting enzyme

Abstract

The human renin-angiotensin system (RAS) plays an essential role in regulating blood pressure and systemic vascular resistance. Renin and angiotensin I-converting enzyme (ACE) are two key enzymes in RAS and have long been recognized as attractive antihypertensive targets. Here, a synthetic strategy was proposed integrating quantitative structure-activity relationship (QSAR), molecular dynamics (MD) simulation and binding free energy analysis to discover novel dual renin and ACE peptidic inhibitors. With the strategy a number of candidates were generated virtually, from which eight promising peptides were selected and synthesized for biological assay. Consequently, three peptides (RYLP, YTAWVP and YRAWVL) were successfully identified to have satisfactory inhibitory profile against both renin and ACE with IC values of <1 mM and <10 μM, respectively. Structural analysis and energetic dissection revealed different binding modes of peptide to renin and ACE; a peptide only inserts its C-terminus into the active site of ACE, whereas the whole peptide packs tightly against renin. In addition, when limited to structural diversity it is hard to reconcile the renin and ACE inhibitory activities of short peptides such as dipeptides. These findings can be used to guide peptide optimization with improved biological activity.

Isolation and Characterization of Angiotensin Converting Enzyme Inhibitory Peptides from Peach Seed Hydrolysates: In Vivo Assessment of Antihypertensive Activity

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Molecular docking, 3D-QSAR and structural optimization on imidazo-pyridine derivatives dually targeting AT1 and PPARγ

“…When the parameters of the model calculated, Partial Least Squares (PLS) method was adopted to derive linear relationships between the bioactivity values and the CoMFA descriptors [37, 45]. PLS analysis is generally performed in two stages.…”

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“…An advantage of biologically active peptides is that they very rarely interact with other drug substances. The use of a specific peptide drugs is a potential alternative therapy for the treatment of hypertension (13). Along with this, an increased interest in foods and dietary supplements enriched with peptides with anti-hypertensive action.…”