Virtual Screening of Brazilian Biodiversity-Derived Natural Products Targeting α-synuclein Prion-like Aggregation

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder and is characterized by the pathological accumulation of misfolded α-synuclein (α-syn) aggregates. Currently, no curative or preventive therapies are available, and existing pharmacological interventions offer only limited and temporary symptomatic relief. Natural products (NPs) that modulate protein misfolding and aggregation represent promising therapeutic strategies. Brazil’s rich biodiversity constitutes a unique reservoir of structurally diverse chemical scaffolds. In this study, we combined molecular docking and ADMET profile prediction to virtually screen the NuBBE database — a chemically diverse collection of NPs derived from Brazilian biodiversity—with the aim of identifying novel inhibitors of α-syn–induced neurotoxicity for experimental validation. A total of 2,363 compounds were docked into the α-syn protofibril structure using AutoDock Vina, and the top 50 hits, with binding affinities ranging from –8.8 to –7.1 kcal/mol, were selected. All 50 hits formed key interactions with the Tyr39 “valve” residue in the N-terminal pocket, which alternates between narrow (open) and wide (closed) conformations. To evaluate ADMET properties, these hits were analyzed using the Admet_Risk module in ADMET Predictor® 13. Risk scores ranged from 2.9 to 10, and a cutoff score of ≤6.5 was applied to select the safest and most bioavailable candidates. Thirty high-risk compounds (scores >6.5) were excluded, and 20 hits were prioritized for experimental validation via biophysical assays and imaging techniques. Notably, sesamin from Raulinoa echinata exhibited the lowest Admet_Risk score (2.9) and a docking score of –7.217 kcal/mol, identifying it as the most promising candidate for further investigation.