Quantum-chemistry-guided identification of a dual-functional cod-derived peptide targeting oxidative stress and inflammation.
Xin Xuan-Ying, Park Sungkwon, Wang Hao-Wen, Hur Sunjin, Li Xiang-Zi, Choi Seongho
Abstract
OBJECTIVE: To identify dual-functional peptides from cod protein targeting oxidative stress and inflammation by investigating their electronic structure-activity relationships through an integrated computational and experimental approach. METHODS: From 1206 in silico hydrolyzed cod peptides, candidates were screened via dual-target docking (Keap1/TLR4), DFT calculations, and MD simulations, followed by validation in LPS-induced RAW264.7 cells. RESULTS: The tetrapeptide YGDF was identified as a lead candidate. In silico analysis predicted that the tetrapeptide YGDF possesses a strong electron-donating propensity due to its unique electronic topology. Fukui function analysis suggested a 'nucleophilic-electrophilic' dual-center distribution, where the Tyr1 site acts as a radical scavenger while the Asp3/Phe4 residues facilitate anchoring within the TLR4 binding pocket. Experimental validation confirmed that YGDF (100 μg/mL) effectively suppressed the NF-κB inflammatory cascade and activated the Nrf2 antioxidant pathway in LPS-induced RAW264.7 cells. Specifically, YGDF inhibited the mRNA expression of iNOS and COX-2 by approximately 75% and 80%, respectively, and induced a 30-fold increase in HO-1 transcription. CONCLUSION: YGDF acts as a dual-target regulator, and its bioactivity is closely associated with the electronic spatial distribution predicted by Fukui function analysis.
Key Findings
- The tetrapeptide YGDF from cod protein was identified as a dual-functional candidate targeting oxidative stress and inflammation.
- In silico analysis showed YGDF has strong electron-donating properties with a nucleophilic-electrophilic dual-center distribution, enabling radical scavenging and TLR4 binding.
- Experimental validation demonstrated YGDF suppressed NF-κB inflammatory cascade, inhibited iNOS and COX-2 mRNA expression by ~75% and ~80%, and induced a 30-fold increase in HO-1 transcription via Nrf2 activation.
Clinical Significance
The peptide YGDF could serve as a novel therapeutic agent to simultaneously reduce oxidative stress and inflammation by activating the Nrf2 antioxidant pathway and inhibiting pro-inflammatory signaling, potentially benefiting diseases driven by these processes.
Citation
Xin Xuan-Ying, Park Sungkwon, Wang Hao-Wenet al.. Quantum-chemistry-guided identification of a dual-functional cod-derived peptide targeting oxidative stress and inflammation. Bioorganic chemistry. 2026-Aug-15.