{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T02:39:05Z","timestamp":1768271945404,"version":"3.49.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T00:00:00Z","timestamp":1763424000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioinform."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fbinf.2025.1716375","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T06:22:11Z","timestamp":1763446931000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Food-derived linear vs. rationally designed cyclic peptides as potent TNF-alpha inhibitors: an integrative computational study"],"prefix":"10.3389","volume":"5","author":[{"given":"Manisha","family":"Shah","sequence":"first","affiliation":[]},{"given":"Sivakumar","family":"Arumugam","sequence":"additional","affiliation":[]}],"member":"1965","published-online":{"date-parts":[[2025,11,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1016\/S0022-3549(15)00188-4","article-title":"Comparison of linear and cyclic his-ala-val peptides in modulating the blood-brain barrier permeability: impact on delivery of molecules to the brain","volume":"105","author":"Alaofi","year":"2016","journal-title":"J. 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