Front Bioinform. 2025 Nov 18;5:1716375. doi: 10.3389/fbinf.2025.1716375. eCollection 2025.
ABSTRACT
INTRODUCTION: Tumor necrosis factor-alpha (TNF-alpha) is a central mediator of chronic inflammation and a validated therapeutic target in atherosclerosis and related cardiovascular disorders. Peptide therapeutics offer high specificity and low toxicity; however, few natural sequences have been optimized for durable TNF-alpha inhibition.
METHODS: A dual in silico strategy was employed to identify potent inhibitors: (i) virtual screening of experimentally validated food-derived bioactive peptides and (ii) rational design of an N-C cyclized and disulfide-bridge peptide based on the TNF-alpha-TNFR1 interface. Molecular docking, 200-ns molecular dynamics simulations, and MM/PBSA free-energy analyses were performed.
RESULTS: The selected peptides exhibited strong and persistent interactions with key TNF-alpha residues, particularly Tyr119. The cyclic analogue demonstrated deeper free-energy minima, higher binding affinity, and more stable hydrogen-bond networks than the linear sequence. ADMET profiling revealed superior metabolic stability, reduced plasma clearance, and no predicted cardiotoxicity.
DISCUSSION: These results indicate that dietary peptides can serve as templates for TNF-alpha inhibition, and interface-guided cyclization rationally enhances stability, binding affinity, and drug-like properties. This study provides a mechanistic framework for developing food-derived peptides as next-generation TNF-alpha antagonists and supports United Nations SDGs 3 and 9 by promoting innovative, low-toxicity therapeutics for chronic inflammation and cardiovascular diseases.
PMID:41341997 | PMC:PMC12669231 | DOI:10.3389/fbinf.2025.1716375