Abstract
Background: Disability-linked neurodegeneration involves cholinergic dysfunction, amyloidogenesis, glutamatergic excitotoxicity, and dopaminergic imbalance, highlighting the need for multi-target modulation. Catharanthus roseus contains a diverse array of metabolites with potential polypharmacological properties. Methods: We curated 318 Catharanthus roseus metabolites and performed structure-based virtual screening against five CNS targets, namely BACE1, AChE, MAO-B, NMDAR, and D1, using target-specific positive controls. Cross-target intersection ranking nominated three hits. We assessed dynamic stability by 200 ns all-atom molecular dynamics simulations (MDS) and MM/PBSA; ADMET-AI profiled CNS-relevant properties. Results: The three metabolites (PubChem CIDs 485711, 56964592, and 162963996) repeatedly ranked among top binders across targets. All five protein-ligand complexes reached stable MD plateaus (RMSD < ~0.30 nm) with sustained key interactions; BACE1 and AChE showed the highest contact persistence and most favorable ΔG_total/ligand-efficiency. Conclusions: Convergent docking, MDS, and MM/PBSA support these metabolites as tractable multi-target leads, with BACE1/AChE prioritized for enzyme-level validation and the remaining targets for follow-up studies.