AUTHOR=Shah Manisha , Arumugam Sivakumar 

TITLE=Food-derived linear vs. rationally designed cyclic peptides as potent TNF-alpha inhibitors: an integrative computational study

JOURNAL=Frontiers in Bioinformatics

VOLUME=Volume 5 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/bioinformatics/articles/10.3389/fbinf.2025.1716375

DOI=10.3389/fbinf.2025.1716375

ISSN=2673-7647

ABSTRACT=IntroductionTumor 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.MethodsA 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.ResultsThe 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.DiscussionThese 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.