Virtual Screening–Derived Computational Lead Candidates for MAO-B Inhibition in Parkinson’s Disease: Pathway-Informed Docking, Molecular Dynamics, DFT and ADMET Evaluation

Monoamine oxidase B (MAO-B) is a clinically validated target in Parkinson’s disease (PD), but docking rank alone is insufficient to establish a CNS-directed inhibitor. We integrated MAOB-related pathway context, domain-resolved structural annotation, GNINA virtual screening, predicted blood–brain barrier (BBB) permeation, molecular dynamics (MD), density functional theory (DFT) and ADMET assessment to nominate hypothesis-stage computational candidates. A pharmacophore-derived input collection 2870 entries was subjected to virtual screening; a curated BBB-positive, favorable Vina/CNN-affinity shortlist yielded PubChem CIDs 143667968, 42876521 and 1232631. The three candidates had similar reported GNINA scores. In single 100 ns MD trajectories, CID 42876521 displayed frequent protein–ligand hydrogen bonds, whereas CID 143667968 displayed almost none and reduced aromatic-cage fluctuation. CID 143667968 also had the smallest gas-phase HOMO–LUMO gap. All three compounds carried predicted mutagenicity, carcinogenicity and hERG alerts. CID 42876521 is therefore prioritized for validation, CID 143667968 is retained as a complementary hypothesis and CID 1232631 as a backup scaffold. These results define a preliminary, multi-parameter prioritization framework.