Melatonin and Related Compounds as Enzymatic Antioxidants:A Comprehensive Theoretical StudyOA

Objectives:Oxidative stress(OS)plays a pivotal role in chronic and neurodegenerative diseases,which has sparked interest in molecules that modulate redox-regulating enzymes.Melatonin and its metabolites exhibit antioxidant properties;however,their molecular mechanisms of enzymatic and transcriptional modulation remain unclear.This study aimed to investigate,through an exploratory in silico approach,the interactions of melatonin and related compounds with OS-related enzymes to generate hypotheses about their role in cellular redox control.Methods:A rational selection of antioxidant,pro-oxidant,and transcriptional targets was performed.Ligands were optimized at the DFT level(M05-2X/6-311+G(d,p))and docked to OS related enzymes.Docking results were analyzed using polygenic antioxidant indices(PAOX)and a similarity interaction index(SSI).Molecular dynamics simulations of selected complexes provided additional insight into potential ligand-protein interaction mechanisms.Results:In silico analyses revealed that N1-acetyl-5-methoxykynuramine(AMK),N1-acetyl-N2-formyl-5-methoxykynuramine(AFMK),and 3-hydroxymelatonin(3OH-M)could partially inhibit pro-oxidant enzymes such as neuronal nitric oxide synthase(nNOS),5-lipoxygenase(5-LOX),thioredoxin reductase(TrxR),and nicotinamide adenine dinucleotide phosphate oxidase(NOX5).The N-(2-(2-acetyl-6,7-dihydroxy-1H-indol-3-yl)ethyl)acetamide(IIcD)and N-(2-(6-hydroxy-7-mercapto-5-methoxy-1H-indol)ethyl)acetamide(dM38)derivatives could potentially stabilize superoxide dismutase(SOD1)and catalase(CAT)enzymes,respectively.Finally,AFMK and dM38 showed consistent interactions with transcriptional regulators,particularly peroxisome proliferator-activated receptor alpha(PPARα)and Kelchlike ECH-associated protein 1(KEAP1).Conclusion:These studies about melatonin-related compounds support a multifactorial profile of redox modulation and provide mechanistic hypotheses for future experimental validation.Among these approaches,the interaction-similarity index is introduced as a novel tool to facilitate the identification of promising redox-active candidates.