DeepAngio AI model identifies novel ACE-inhibitory peptides LLRP, LHWPR, RFLR from tuna hydrolysate

Conventional methods for discovering angiotensin-converting enzyme (ACE) inhibitory peptides are often inefficient, yielding suboptimal activity and requiring extensive optimization. Hypertension, a major global health concern, is frequently managed by ACE inhibitors, which block the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. While synthetic ACE inhibitors are effective, there's growing interest in natural, food-derived peptides as safer alternatives with fewer side effects. The challenge lies in efficiently identifying and producing these bioactive peptides, addressing a critical gap in developing functional foods and nutraceuticals for blood pressure management.

Researchers developed DeepAngio, a novel computational model, to streamline the preparation and screening of ACE-inhibitory peptides. The model's performance was validated using 10-fold cross-validation. Following computational screening, DeepAngio guided the directional preparation of tuna meat hydrolysates. From these hydrolysates, three specific peptides – LLRP, LHWPR, and RFLR – were isolated and their ACE inhibitory activity was experimentally confirmed. The mechanism of ACE inhibition for each peptide was characterized using spectroscopic analysis and molecular docking simulations to understand their binding modes.

The DeepAngio model demonstrated high predictive performance, achieving 98.80% accuracy, 99.63% precision, and 96.44% specificity in screening ACE-inhibitory peptides. For classification tasks, it showed 88.24% accuracy, 86.76% precision, and 95.16% specificity. The tuna meat hydrolysates, prepared with DeepAngio's guidance, exhibited notable ACE inhibitory activity with an IC50 of 31.27 ± 0.72 µg/mL. Three novel potent ACE inhibitory peptides were successfully screened and isolated:

LLRP (IC50, 3.44 ± 0.19 µM), LHWPR (IC50, 17.67 ± 1.53 µM), and RFLR (IC50, 42.52 ± 7.50 µM). These peptides inhibited ACE activity through distinct mechanisms: LLRP and RFLR showed mixed-competitive inhibition, while LHWPR exhibited competitive inhibition, forming stable complexes with the enzyme, as confirmed by spectroscopic and molecular docking analyses.