Identification of natural MAO-B inhibitors with enhanced binding and dynamic stability: Implications for Parkinson's disease therapy.

By a comprehensive in silico workflow, this study investigates promising natural inhibitors of monoamine oxidase B (MAO-B) relevant to Parkinson's disease therapy. Selegiline is used as a pharmacophore scaffold to screen a large ZINC15 natural product library by drug-likeness, PAINS, ADMET, filters, followed by pharmacophore mapping, consensus docking, and MD simulations. This technique efficiently leads over 200,000 compounds to four hits (Lig-473, Lig-1781, Lig-2148, and Lig-2698), all of which demonstrated stronger binding affinities than selegiline. Docking studies showed that Lig-473 and Lig-2148 penetrate deeply into the FAD/substrate-binding cavity and interact with the conserved residues, while Lig-1781 and Lig-2698 mainly occupy the entrance region, blocking substrate access. MD simulations revealed Lig-473 and Lig-2148 form stable MAO-B complexes. MM/PBSA identified Lig-473 as the strongest binder. Translational relevance confirms their viability as safe, effective drug candidates with favorable ADMET profiles and minimal off-target effects. In total, these findings highlight Lig-473 and Lig-2148 as promising natural scaffolds for MAO-B inhibition, suggesting them for further experimental validation.