Bioactive phytoconstituent millettone as a potential inhibitor of catechol O-methyltransferase: Implications for neuroprotective therapy in Parkinson's disease

Catechol O-methyltransferase (COMT) is a cation-dependent enzyme essential for the metabolism of catechols, including dopamine, norepinephrine, caffeine, and estrogens. COMT is highly expressed in tissues such as the brain, liver, and erythrocytes, and its elevated levels in dopaminergic neurons are implicated in Parkinson's disease. Considering it as a promising target for drug development against Parkinson's disease, this study employed in silico screening of plant-derived compounds from the IMPPAT 2.0 data base to identify potential COMT inhibitors. Compounds were initially filtered out based on their pharmacokinetic properties and binding affinities. Further screening included ligand–receptor interaction calculations, pan-assay interface compounds filtering, ADMET analysis, and biological activity prediction, followed by stability assessments to select the most promising phytochemicals. Millettone emerged as a top candidate, demonstrating high affinity and specific binding interactions with COMT. Comprehensive evaluations, including all-atom molecular dynamics simulations and essential dynamics analysis, further supported millettone's stability and effectiveness as a potential COMT inhibitor. These findings suggest that millettone is a strong candidate for further experimental studies, with potential application as an anti-Parkinson's therapeutic targeting COMT. Significance Statement: This study identified a plant-based natural compound, millettone, as a potential catechol O-methyltransferase inhibitor through in silico screening and molecular dynamics simulations. Its strong binding and stability suggest therapeutic potential for Parkinson's disease, warranting further experimental validation.