Discovery of Novel Small-Molecule Modulators of α-Synuclein Aggregation via Symmetric Docking

The accumulation of misfolded α-synuclein (α-syn) aggregates is the primary pathological hallmark of synucleinopathies, with Parkinson’s disease (PD) representing the most prevalent disorder within this group. Currently, no curative or disease-modifying therapies are available, and existing pharmacological treatments provide only symptomatic relief. Growing evidence suggests that many small molecules can modulate the neurotoxicity associated with amyloid fibrils and intermediate aggregates, highlighting the potential of natural product–derived scaffolds. Recent cryo-EM structures of α-syn complexed with small molecules demonstrate that ligands can pack into continuous stacks that mirror the rotational and translational symmetry of the underlying fibril. Intriguingly, these structures often feature minimal direct contact with the fibril backbone, relying instead on inter-ligand stacking interactions. To address this challenge, SymDOCK was developed for the DOCK3.8 software package. By imposing the fibril's symmetry on any given ligand geometry and ensuring there are no ligand–ligand van der Waals clashes, SymDOCK adapts structure-based virtual screening to the unique architecture of amyloid fibrils, enabling the successful identification of high-affinity hits from large chemical databases In this study, we systematically explored Brazilian chemical space—including both natural and synthetic molecules—using SymDOCK to identify novel modulators of the α-syn aggregation pathway. Specifically, we performed symmetric docking-based virtual screening of the NuBBE database (NuBBEDB), a chemically diverse collection of natural products derived from Brazilian biodiversity, and the IRACEMA database, which comprises molecules assembled in Brazil. Symmetric docking studies were conducted using the α-syn protofibril structure (PDB ID: 7YNN), in which ThT molecules are resolved in stacked arrangements within the fibrils. The symmetric extension of DOCK 3.8 (SymDOCK) was employed to facilitate ligand docking against protein fibrils, considering their rotational and translational symmetry and incorporating a crude ligand–ligand interaction energy term. A docking score cutoff of ≤ −20.0 was applied to select hits. In addition, the Admet_Risk module implemented in ADMET Predictor® 13 was used to evaluate pharmacokinetic and toxicity-related risks, applying a cutoff score of ≤ 6.5. Among the top-ranked candidates, representative examples include vismiaquinone (NuBBE_2088), nobiletin (NuBBE_1218), tetramethylscutellarein (NuBBE_1215), and the sulfonamide derivatives IRA-3 and IRA-6.

This work was supported by CNPQ and by the FAPERJ.