A strategy to boost xanthine oxidase and angiotensin converting enzyme inhibitory activities of peptides via molecular docking and module substitution

• Published in: Food chemistry 2024-06, Vol.442, p.138401-138401, Article 138401
• Main Authors: Meng, Pengfei, Wang, Yanxin, Huang, Yumeng, Liu, Tong, Ma, Mingxia, Han, Jiaojiao, Su, Xiurong, Li, Wenjun, Wang, Yanbo, Lu, Chenyang
• Format: Article
• Language: English
• Subjects: Activity boosting strategy; Angiotensin-converting enzyme inhibitory; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Module substitution; Molecular docking; Molecular Docking Simulation; Peptide; Peptides - pharmacology; Peptidyl-Dipeptidase A; Uric Acid; Xanthine Oxidase; Xanthine oxidase inhibitory
• ISSN: 0308-8146; 1873-7072
• DOI: 10.1016/j.foodchem.2024.138401

•GP and KE were identified as low- and high-contribution modules of XOD inhibitory activity.•Substituting low-contribution modules with high-contribution modules boosted the XOD inhibitory activity of the natural peptide.•This improvement was attributed to the inhibition of uric acid biosynthesis and regulation of signaling pathways.•Module-substitution increased ACE inhibitory activity of natural peptides. Molecular docking and activity evaluation screened the dipeptide module GP with low xanthine oxidase (XOD) inhibitory activity and modules KE and KN with high activity, and identified them as low- and high-contribution modules, respectively. We hypothesized the substitution of low-contribution modules in peptides with high contributions would boost their XOD inhibitory activity. In the XOD inhibitory peptide GPAGPR, substitution of GP with both KE and KN led to enhanced affinity between the peptides and XOD. They also increased XOD inhibitory activity (26.4% and 10.3%) and decreased cellular uric acid concentrations (28.0% and 10.4%). RNA sequencing indicated that these improvements were attributable to the inhibition of uric acid biosynthesis. In addition, module substitution increased the angiotensin-converting enzyme inhibitory activity of GILRP and GAAGGAF by 84.8% and 76.5%. This study revealed that module substitution is a feasible strategy to boost peptide activity, and provided information for the optimization of hydrolysate preparation conditions.