Chemical repair of oxidized aromatic amino acids by monohydroxylated 2-pyridones

Abstract

The oxidative modification of tryptophan and tyrosine residues in proteins has been strongly associated with the onset and progression of neurodegenerative disorders, such as Alzheimer’s disease and amyotrophic lateral sclerosis. Consequently, the identification of small molecules capable of repairing these oxidized residues is of considerable medicinal interest. In this study, the antioxidant activity of four hydroxy-2-pyridones against tyrosyl and tryptophanyl radicals was investigated in silico using density functional theory, with the aim of elucidating their structure–activity relationships at the molecular level. Thermochemical analyses were conducted to evaluate the most favorable repair pathways, focusing on formal hydrogen transfer (FHT) and single electron transfer (SET) processes. For exergonic reactions, kinetic parameters were determined within the quantum mechanics-based overall free radical scavenging activity (QM-ORSA) protocol, providing predictive data on radical-scavenging efficiency. The results indicate that three of the tested pyridones can repair the tyrosyl radical and that two of them react at rates comparable with the dityrosine formation, thereby competing with this deleterious pathway. In contrast, all four pyridones are able to reduce the tryptophanyl radical, although the calculated kinetics suggest that they may not efficiently suppress the Trp–Trp cross-linking in small peptides. Mechanistic analysis further revealed that FHT proceeds through proton-coupled electron transfer for tyrosyl radical repair, whereas tryptophanyl radical repair involves a proton–electron sequential transfer mechanism. These findings establish hydroxy-2-pyridones as promising scaffolds for the rational design of neuroprotective antioxidants and provide molecular insights that may guide the development of new therapeutic agents targeting oxidative stress.