Ligand-Based Discovery of a Small Molecule as Inhibitor of α-Synuclein Amyloid Formation
De Luca, Laura (University of Messina. Department of Chemical, Biological, Pharmaceutical and Environmental Sciences)
Vittorio, Serena (University of Messina. Department of Chemical, Biological, Pharmaceutical and Environmental Sciences)
Peña Díaz, Samuel (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Pitasi, Giovanna (University of Messina. Department of Chemical, Biological, Pharmaceutical and Environmental Sciences)
Fornt Suñé, Marc (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Bucolo, Federica (University of Messina. Department of Chemical, Biological, Pharmaceutical and Environmental Sciences)
Ventura, Salvador (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Gitto, Rosaria (University of Messina. Department of Chemical, Biological, Pharmaceutical and Environmental Sciences)

Date:	2022
Abstract:	α-Synuclein (α-Syn) aggregates are implicated in Parkinson's disease (PD), so inhibitors of α-Syn aggregation have been intensively explored. It has been demonstrated that small molecules might be able to reduce α-Syn aggregation in fibrils, thus exerting neuroprotective effects in models of PD. To expand our knowledge about the structural requirements for blocking the recognition process into the oligomeric assembly of α-Syn aggregates, we performed a ligand-based virtual screening procedure using two well-known α-Syn aggregation inhibitors, SynuClean-D and ZPD-2, as query compounds. A collection of thirty-four compounds bearing distinct chemical functionalities and mutual chemical features were studied in a Th-T fluorescence test, thus identifying 5-(2,6-dinitro-4-(trifluoromethyl)benzyl)-1-methyl-1H-tetrazole (named MeSC-04) as a potent α-Syn amyloid formation inhibitor that demonstrated similar behavior when compared to SynuClean-D in the thioflavin-T-monitored kinetic assays, with both molecules reducing the number and size of amyloid fibrils, as evidenced by electron microscopy. Molecular modeling studies suggested the binding mode of MeSC-04 through the identification of putative druggable pockets on α-syn fibrils and a subsequent consensus docking methodology. Overall, this work could furnish new insights in the development of α-Syn amyloid inhibitors from synthetic sources.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Alpha-synuclein ; Parkinson's disease ; Small molecule ; Virtual screening ; Binding site prediction ; Th-T fluorescence assay
Published in:	International journal of molecular sciences, Vol. 23, Issue 23 (November 2022) , art. 14844, ISSN 1422-0067

DOI: 10.3390/ijms232314844
PMID: 36499173

14 p, 3.0 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Biotecnologia i de Biomedicina (IBB)
Articles > Research articles
Articles > Published articles