@Article{biocell.2025.071635,
AUTHOR = {Luis Felipe HernáNdez-Ayala, Russel J. Reiter, Annia Galano},
TITLE = {Melatonin and Related Compounds as Enzymatic Antioxidants: A Comprehensive Theoretical Study},
JOURNAL = {BIOCELL},
VOLUME = {50},
YEAR = {2026},
NUMBER = {1},
PAGES = {--},
URL = {http://www.techscience.com/biocell/v50n1/65605},
ISSN = {1667-5746},
ABSTRACT = { <b>Objectives:</b> 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 <i>in silico</i> approach, the interactions of melatonin and related compounds with OS-related enzymes to generate hypotheses about their role in cellular redox control. <b>Methods:</b> 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 (<i>P</i><sup><i>AOX</i></sup>) and a similarity interaction index (<i>S</i><sub><i>SI</i></sub>). Molecular dynamics simulations of selected complexes provided additional insight into potential ligand–protein interaction mechanisms. <b>Results:</b> <i>In silico</i> analyses revealed that N<sup>1</sup>-acetyl-5-methoxykynuramine (AMK), N<sup>1</sup>-acetyl-N<sup>2</sup>-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). <b>Conclusion:</b> 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.},
DOI = {10.32604/biocell.2025.071635}
}