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

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 Kelch-like 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.