Rational design of small molecules able to inhibit α-synuclein amyloid aggregation for the treatment of Parkinson’s disease

Serena Vittorio*, Ilenia Adornato, Rosaria Gitto, Samuel Peña-Díaz, Salvador Ventura, Laura De Luca*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

19 Citations (Scopus)

Abstract

Parkinson’s disease is one of the most common neurodegenerative disorders in elderly age. One of the mechanisms involved in the neurodegeneration appears related to the aggregation of the presynaptic protein alpha synuclein (α-syn) into toxic oligomers and fibrils. To date, no highly effective treatment is currently available; therefore, there is an increasing interest in the search of new therapeutic tools. The modulation of α-syn aggregation represents an emergent and promising disease-modifying strategy for reducing or blocking the neurodegenerative process. Herein, by combining in silico and in vitro screenings we initially identified 3-(cinnamylsulfanyl)-5-(4-pyridinyl)-1,2,4-triazol-4-amine (3) as α-syn aggregation inhibitor that was then considered a promising hit for the further design of a new series of small molecules. Therefore, we rationally designed new hit-derivatives that were synthesised and evaluated by biological assays. Lastly, the binding mode of the newer inhibitors was predicted by docking studies.

Original languageEnglish
Pages (from-to)1727-1735
Number of pages9
JournalJournal of Enzyme Inhibition
Volume35
Issue number1
DOIs
Publication statusPublished - 1 Jan 2020

Keywords

  • Parkinson’s disease
  • aggregation inhibitors
  • alpha-synuclein
  • docking studies
  • ligand-based pharmacophore

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