Hydrophobic-Driven COMT Inhibition by Coumarin from Mucuna pruriens: Docking, Molecular Dynamics, and Binding Free Energy Analysis in Parkinson’s Disease

Abstract

The primary mechanism for dopamine degradation depends on the activity of catechol-O-methyltransferase (COMT) enzyme. The COMT inhibition may improve dopamine transmission in patients with Parkinson’s disease (PD). The medicinal herb Mucuna pruriens (MP) protects brain cells by inhibiting COMT activity with its active components. Researchers conducted in silico screening to assess the efficacy of MP phytochemicals in inhibiting COMT. Overall, 13 phytoconstituents were selected through the IMPPAT 2.0 database and subjected to molecular docking (AutoDock Vina) to reveal how selected compounds interacted with the COMT crystal structure (PDB ID: 6I3D). The compounds exhibited stronger binding than both the co-crystallized ligand and the reference drug, with coumarin achieving the highest docking score of −7.6 kcal/mol, followed by linoleic acid and oleic acid at −7.5 and −7.4 kcal/mol, respectively. Coumarin binds to the COMT active site by forming hydrogen bonds with two essential amino acids, Trp143 and Ile91. The molecular dynamics simulations showed that the protein–ligand complex remained stable, with the backbone root-mean-square deviation (RMSD) fluctuating between 1.3 and 1.6 Å. The root-mean-square fluctuation (RMSF) results, combined with the protein–ligand interactions, demonstrated that the ligand maintained stable contact through binding interactions, including both hydrophobic interactions and water-mediated hydrogen bonds with Glu90. The molecular mechanics–generalized born surface area (MM–GBSA) determined that the system achieved a favorable binding free energy of −75.19 ± 4.96 kcal/mol, driven by hydrophobic stabilization via van der Waals and lipophilic interactions.: The natural compound Coumarin from MP shows potential as a COMT inhibitor for the treatment of PD.