Quantum-chemistry-guided identification of a dual-functional cod-derived peptide targeting oxidative stress and inflammation

초록

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.

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