Melatonin and Related Compounds as Enzymatic Antioxidants: A Comprehensive Theoretical Study
Luis Felipe HernáNdez-Ayala1, Russel J. Reiter2, Annia Galano1,*
1 Departamento de Química, Universidad Autónoma Metropolitana-Iztapalapa, Av. Ferrocarril San Rafael Atlixco 186, Col. Leyes de Reforma 1 A Sección, Alcaldía Iztapalapa, México City, 09310, México
2 Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, TX 78229, USA
* Corresponding Author: Annia Galano. Email: 
(This article belongs to the Special Issue: Melatonin and Mitochondria: Exploring New Frontiers)
BIOCELL https://doi.org/10.32604/biocell.2025.071635
Received 09 August 2025; Accepted 03 November 2025; Published online 26 November 2025
Abstract
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 N
1-acetyl-5-methoxykynuramine (AMK), N
1-acetyl-N
2-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.
Keywords
Melatonin; metabolites; antioxidant enzymes; pro-oxidant enzymes; transcription factors; molecular docking
Open Access
Login
Register
Submit a Paper
Propose a Special lssue
Download PDF
Supplementary Material File
Downloads
Citation Tools
