Optimization of a small molecule inhibitor of secondary nucleation in α-synuclein aggregation.
Published version
Peer-reviewed
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Repository DOI
Type
Article
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Authors
Staats, Roxine
Brotzakis, Z Faidon
Chia, Sean
Horne, Robert I
Vendruscolo, Michele
Abstract
Parkinson's disease is characterised by the deposition in the brain of amyloid aggregates of α-synuclein. The surfaces of these amyloid aggregates can catalyse the formation of new aggregates, giving rise to a positive feedback mechanism responsible for the rapid proliferation of α-synuclein deposits. We report a procedure to enhance the potency of a small molecule to inhibit the aggregate proliferation process using a combination of in silico and in vitro methods. The optimized small molecule shows potency already at a compound:protein stoichiometry of 1:20. These results illustrate a strategy to accelerate the optimisation of small molecules against α-synuclein aggregation by targeting secondary nucleation.
Description
Peer reviewed: True
Keywords
Parkinson’s disease, docking, drug discovery, kinetic theory, secondary nucleation
Journal Title
Front Mol Biosci
Conference Name
Journal ISSN
2296-889X
2296-889X
2296-889X
Volume Title
10
Publisher
Frontiers Media SA
Publisher DOI
Sponsorship
Wellcome Trust (203249/Z/16/Z)