Sarcouncil Journal of Applied Sciences Aims & Scope

Abstract: Reactive oxygen species (ROS) are central mediators of oxidative stress, driving pathological processes in cardiovascular, neurodegenerative, and metabolic disorders. Melatonin and its derivatives have emerged as potent spin-trapping antioxidants capable of neutralizing diverse ROS via cascade scavenging mechanisms. While experimental studies provide valuable insights, the fleeting nature of radical intermediates necessitates computational approaches to elucidate mechanisms and predict reactivity. This systematic review critically evaluates computational strategies employed between 2009 and 2025 to model the spin-trapping activity of melatonin derivatives, with emphasis on accuracy and predictive power. Across 42 eligible studies, density functional theory (DFT) dominated, particularly M06-2X and ωB97XD, which outperformed legacy functionals such as B3LYP in reproducing thermodynamic and kinetic parameters benchmarked against CCSD(T) and experimental electron paramagnetic resonance (EPR) data. Basis set selection (e.g., aug-cc-pVTZ, def2-TZVP) and solvation treatment (SMD, PCM, and hybrid explicit–implicit models) strongly influenced predictive reliability. Hydrogen atom transfer (HAT), single electron transfer (SET), and radical adduct formation (RAF) emerged as the primary mechanistic pathways, with HAT displaying the most consistent alignment with experimental kinetics. Notable gaps include limited modeling of diradical species such as singlet oxygen, underrepresentation of peroxynitrite, and insufficient explicit solvation studies to capture hydrogen-bonding dynamics. The integration of machine learning with quantum chemical descriptors shows promise for accelerating structure–activity predictions. Overall, computational chemistry has advanced mechanistic understanding of melatonin-derived spin-trapping but requires standardized protocols and deeper integration with experimental pipelines to enable rational antioxidant design and translational impact.