Analysis of ACE–tetrapeptide binding interaction and screening of potential inhibitory peptides via molecular docking
Miaomiao Wang, Wenyuan Zhang, Bing Li, Xiaoyu Jiang, Wenxuan Li, Hui Zou, Dapeng Li · Food biomacromolecules. · 2025
Abstract Hypertension is a major risk factor for various diseases and poses a significant threat to human health. Angiotensin‐I‐converting enzyme (ACE) is a metal carboxypeptidase that catalyzes the conversion of angiotensin I to angiotensin II, increasing hypertension. Although ACE inhibitors effectively manage hypertension, their long‐term use can cause side effects, necessitating safer alternatives. Food‐derived antihypertensive peptides, especially short peptides, show great potential due to their low toxicity, high bioactivity, and good absorption, yet their therapeutic potential remains underexplored. In this study, we employed a virtual screening strategy to systematically evaluate all possible tetrapeptides (160,000 sequences) and analyzed their interactions with ACE. The results revealed that peptides containing Y, F, R, and W are characteristic amino acids for ACE inhibitors. Interactions including hydrophobic interaction, hydrogen bonding, salt bridges, pi–pi stacking, and pi‐cation all contributed to the tight binding of peptides to ACE. Seven peptides (RWRW, FWRR, WWRR, YWRR, RWRF, RWRY, and RWRR) were synthesized to determine their ACE inhibitory effects, thereby validating the virtual screening method. The results showed that these peptides possess good ACE inhibitory activity, with IC50 values ranging from 18.28 to 145.00 μM. This study provides both theoretical and experimental support for the screening and development of natural peptides.