Optimization of a small molecule inhibitor of secondary nucleation in α-synuclein aggregation.

Published version
Repository DOI

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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
Volume Title
10
Publisher
Frontiers Media SA
Sponsorship
Wellcome Trust (203249/Z/16/Z)