{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T23:03:01Z","timestamp":1790636581347,"version":"4.1.0"},"reference-count":115,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T00:00:00Z","timestamp":1747958400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Sepsis, a life-threatening condition characterized by immune dysregulation and organ damage, remains a significant clinical challenge. Natural antioxidant compounds (NAOs) such as quercetin, EGCG, resveratrol, curcumin, and chlorogenic acid have shown promising anti-inflammatory and anti-apoptotic effects in preclinical models of sepsis and related conditions, yet the molecular mechanisms underlying their actions remain incompletely defined. In this study, we performed comprehensive molecular docking analyses to investigate the binding affinities and interaction profiles of these NAOs with three key proteins central to inflammatory and apoptotic signaling: Toll-like receptor 4 (TLR-4), interleukin-1 receptor-associated kinase 1 (IRAK1), and caspase-3. Our results demonstrate that all five compounds exhibit favorable binding affinities with these targets, forming multiple hydrogen bonds and hydrophobic interactions with critical active site residues. Notably, curcumin and EGCG consistently displayed the strongest binding affinities across the three proteins, with docking scores comparable to or surpassing those of reference inhibitors. Resveratrol demonstrated highly stable binding poses, particularly with caspase-3, while quercetin and chlorogenic acid showed moderate but reproducible affinities. Overall, this study provides new mechanistic insights into how NAOs may target central mediators of inflammation and cell death. Experimental validation is essential to confirm these interactions, assess binding affinities, and fully elucidate the therapeutic potential of NAOs in sepsis.<\/jats:p>","DOI":"10.3390\/molecules30112288","type":"journal-article","created":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T09:58:09Z","timestamp":1747994289000},"page":"2288","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["In Silico Exploration of Natural Antioxidants for Sepsis Drug Discovery"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4731-6398","authenticated-orcid":false,"given":"Celia Mar\u00eda Curieses","family":"Andr\u00e9s","sequence":"first","affiliation":[{"name":"Hospital Cl\u00ednico Universitario of Valladolid, Avenida de Ram\u00f3n y Cajal, 3, 47003 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena Bustamante","family":"Munguira","sequence":"additional","affiliation":[{"name":"Hospital Cl\u00ednico Universitario of Valladolid, Avenida de Ram\u00f3n y Cajal, 3, 47003 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1583-7439","authenticated-orcid":false,"given":"Celia Andr\u00e9s","family":"Juan","sequence":"additional","affiliation":[{"name":"Cinquima Institute and Department of Organic Chemistry, Faculty of Sciences, Valladolid University, Paseo de Bel\u00e9n, 7, 47011 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Lobo","sequence":"additional","affiliation":[{"name":"Institute of Natural Products and Agrobiology (IPNA-CSIC), CSIC-Spanish Research Council, Avda. Astrof\u00edsico Francisco S\u00e1nchez, 3, 38206 San Crist\u00f3bal de la Laguna, Tenerife, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"P\u00e9rez-Lebe\u00f1a","sequence":"additional","affiliation":[{"name":"Valladolid University Foundation, Paseo de Bel\u00e9n, 11, 47011 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4663-5565","authenticated-orcid":false,"given":"Jos\u00e9 Manuel","family":"P\u00e9rez de la Lastra","sequence":"additional","affiliation":[{"name":"Institute of Natural Products and Agrobiology (IPNA-CSIC), CSIC-Spanish Research Council, Avda. Astrof\u00edsico Francisco S\u00e1nchez, 3, 38206 San Crist\u00f3bal de la Laguna, Tenerife, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Wiersinga, W.J., and van der Poll, T. (2022). Immunopathophysiology of human sepsis. EBioMedicine, 86.","DOI":"10.1016\/j.ebiom.2022.104363"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"456","DOI":"10.3390\/epidemiologia5030032","article-title":"The global burden of sepsis and septic shock","volume":"5","author":"Sangiorgio","year":"2024","journal-title":"Epidemiologia"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Miliaraki, M., Briassoulis, P., Ilia, S., Michalakakou, K., Karakonstantakis, T., Polonifi, A., Bastaki, K., Briassouli, E., Vardas, K., and Pistiki, A. (2022). 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