ArticleMolecular pharmaceutics2023
Structure-Based Discovery of Small-Molecule Inhibitors of the Autocatalytic Proliferation of α-Synuclein Aggregates.
Article in Molecular pharmaceutics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 40 citations in OpenAlex.
- α-Synuclein as a molecular link between Parkinson's disease and chronic kidney disease: insights into the kidney-brain axis.Metabolic brain disease · 2026Review
- Identification of potent high-affinity secondary nucleation inhibitors of Aβ42 aggregation from an ultra-large chemical library using deep docking.Molecular systems biology · 2026Article
- Design of Tau Aggregation Inhibitors Using Iterative Machine Learning and a Polymorph-Specific Brain-Seeded Fibril Amplification Assay.Journal of the American Chemical Society · 2025Article
- Charged peptides enriched in aromatic residues decelerate condensate ageing driven by cross-β-sheet formation.Nature communications · 2025Article
- Detecting alpha-synuclein aggregates with small molecules on single-molecule array.Chemical science · 2025Article
- Structure-based discovery of forsythoside A as an effective inhibitor to reduce the neurotoxicity of amyloid β.Communications chemistry · 2025Article
- Ligands for Protein Fibrils of Amyloid-β, α-Synuclein, and Tau.Chemical reviews · 2025Review
- Using a stable protein scaffold to display peptides that bind to alpha-synuclein fibrils.Protein science : a publication of the Protein Society · 2025Article
- The Role of α-Synuclein-DNAJB6b Coaggregation in Amyloid Suppression.ACS chemical neuroscience · 2025Article
- Detection of protein oligomers with nanopores.Nature reviews. Chemistry · 2025Review
- Small Molecules, α-Synuclein Pathology, and the Search for Effective Treatments in Parkinson's Disease.International journal of molecular sciences · 2024Review
- Pharmacological inhibition of α-synuclein aggregation within liquid condensates.Nature communications · 2024Article
- Discovery of potent inhibitors of α-synuclein aggregation using structure-based iterative learning.Nature chemical biology · 2024Article
- Using Generative Modeling to Endow with Potency Initially Inert Compounds with Good Bioavailability and Low Toxicity.Journal of chemical information and modeling · 2024Article
- Liquid-liquid phase separation and conformational strains ofFrontiers in molecular neuroscience · 2024Review
- Ultrastructures of α-Synuclein Filaments in Synucleinopathy Brains and Experimental Models.Journal of movement disorders · 2024Article
- Multiplexed Digital Characterization of Misfolded Protein Oligomers via Solid-State Nanopores.Journal of the American Chemical Society · 2023Article
- Secondary Processes Dominate the Quiescent, Spontaneous Aggregation of α-Synuclein at Physiological pH with Sodium Salts.ACS chemical neuroscience · 2023Article
- Inhibition of Protein Aggregation and Endoplasmic Reticulum Stress as a Targeted Therapy for α-Synucleinopathy.Pharmaceutics · 2023Review
- Exploration and Exploitation Approaches Based on Generative Machine Learning to Identify Potent Small Molecule Inhibitors of α-Synuclein Secondary Nucleation.Journal of chemical theory and computation · 2023Article
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 2 countries.
Funding
Abstract
The presence of amyloid fibrils of α-synuclein is closely associated with Parkinson's disease and related synucleinopathies. It is still very challenging, however, to systematically discover small molecules that prevent the formation of these aberrant aggregates. Here, we describe a structure-based approach to identify small molecules that specifically inhibit the surface-catalyzed secondary nucleation step in the aggregation of α-synuclein by binding to the surface of the amyloid fibrils. The resulting small molecules are screened using a range of kinetic and thermodynamic assays for their ability to bind α-synuclein fibrils and prevent the further generation of α-synuclein oligomers. This study demonstrates that the combination of structure-based and kinetic-based drug discovery methods can lead to the identification of small molecules that selectively inhibit the autocatalytic proliferation of α-synuclein aggregates.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.