Antioxidant efficacy of hydroxytyrosol, tyrosol, homovanillic alcohol, and their acetate derivatives in Parkinson's disease: A synergistic computational approach.

Phenolic plant metabolites, including hydroxytyrosol, tyrosol, homovanillic alcohol, and their acetate derivatives, have emerged as potent antioxidants and promising therapeutic candidates for neurodegenerative disorders. These compounds exhibit dual functionality by efficiently scavenging reactive free radicals and targeting key protein residues, thereby alleviating oxidative stress and preventing cellular damage. Using multiscale in silico methodologies, their interactions with peroxyl (ROO•) and hydroperoxyl (HOO•) radicals, as well as with Monoamine Oxidase A (MAO-A), a pivotal enzyme in Parkinson's disease, were systematically investigated. Density Functional Theory (DFT) analyses illustrate radical stabilization pathways, supported by MEP, SD, NBO, FMO, and Fukui function descriptors. Hirshfeld surface analysis (HSA) and QTAIM further reveal strong binding hotspots, predominantly stabilized by conventional hydrogen bonding complemented with hydrophobic non-covalent contacts. ADMET profiling underscored favorable pharmacokinetic properties and drug-likeness. Finally, molecular docking and molecular dynamics (MD) simulations confirmed their stable accommodation within the MAO-A catalytic pocket, highlighting significant binding affinities and critical interacting residues. Overall, these findings establish hydroxytyrosol, tyrosol and homovanillic alcohol derivatives as potential multifunctional neuroprotective agents against Parkinson's disease.