In Silico Exploration of Natural Antioxidants for Sepsis Drug Discovery

• Published in: Molecules (Basel, Switzerland) Vol. 30; no. 11; p. 2288
• Main Authors: Andrés, Celia María Curieses, Munguira, Elena Bustamante, Juan, Celia Andrés, Lobo, Fernando, Pérez-Lebeña, Eduardo, Pérez de la Lastra, José Manuel
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 23.05.2025; MDPI
• Subjects: Acids; Analysis; Antioxidants; Antioxidants - chemistry; Antioxidants - pharmacology; Antioxidants - therapeutic use; Apoptosis; B cells; Caspase 3 - chemistry; Caspase 3 - metabolism; Catechin; Catechin - analogs & derivatives; Cell death; Chlorogenic Acid - chemistry; Chlorogenic Acid - pharmacology; Clinical trials; Computer Simulation; Critical care; Curcumin - chemistry; Curcumin - pharmacology; Cytokine storm; Drug development; Drug Discovery; Enzymes; Fruits; Gram-negative bacteria; Health aspects; Humans; Hydrogen; Hydrogen Bonding; Immunity (Disease); Infection; Inflammation; Interleukin-1 Receptor-Associated Kinases - chemistry; Interleukin-1 Receptor-Associated Kinases - metabolism; Interleukins; Kinases; Ligands; Microbiota; molecular docking; Molecular Docking Simulation; Mortality; normal mode analysis; Oxidative stress; pathogenesis; Pathogens; Pathophysiology; Protein Binding; Proteins; Quercetin - chemistry; Quercetin - pharmacology; Resveratrol; Resveratrol - chemistry; Resveratrol - pharmacology; Sepsis; Sepsis - drug therapy; Sepsis - metabolism; Simulation; Toll-Like Receptor 4 - chemistry; Toll-Like Receptor 4 - metabolism; Tumor necrosis factor-TNF; Germany; Spain; normal mode analysis; pathogenesis; molecular docking; antioxidants; sepsis
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules30112288

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.