In Silico Screening of Natural Bioactive Compounds against MAO-B and AA2A Receptor for Parkinson’s Disease

Parkinson's disease (PD) remains a debilitating neurodegenerative disorder for which disease-modifying pharmacological options are critically lacking. This study presents a multi-stage in silico evaluation of ten structurally diverse flavonoids as potential dual inhibitors of monoamine oxidase B (MAO-B, PDB: 2V5Z) and the adenosine A2A receptor (AA2AR, PDB: 3EML) — two pharmacologically complementary and clinically validated targets in PD. Drug-likeness and blood–brain barrier (BBB) permeability were assessed using SwissADME, followed by molecular docking via AutoDock Vina (PyRx 0.8), MM-GBSA binding free energy rescoring using AMBER22, and 100 ns molecular dynamics (MD) simulations with GROMACS. Docking protocol validity was confirmed by re-docking co-crystallised ligands (RMSD: 1.72 Å for MAO-B; 1.89 Å for AA2AR). Bavachin (MAO-B: −11.5 kcal/mol; AA2AR: −7.9 kcal/mol) and Bavachinin (MAO-B: −10.6 kcal/mol; AA2AR: −7.7 kcal/mol) consistently outperformed the reference drug Safinamide (−9.2 and −7.0 kcal/mol). MM-GBSA rescoring corroborated these findings (Bavachin MAO-B: −13.2 ± 0.7 kcal/mol), and MD simulations confirmed complex stability with key hydrogen bonds maintained at ≥70–80% occupancy over 100 ns. Both lead compounds satisfied all Lipinski RO5 criteria and demonstrated predicted BBB permeability. These supportive computational predictions identify Bavachin and Bavachinin as priority candidates for experimental validation.