Ligand-Based Discovery of a Small Molecule as Inhibitor of α-Synuclein Amyloid Formation

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.

Alpha Synuclein: Neurodegeneration and Inflammation

“…Other high-throughput screening methods followed to identify anti-Syn aggregation compounds [ 198 , 199 ], including some recent ones where known [ 200 ] or innovative methods [ 201 , 202 ] were applied. Numerous potential candidates to interfere with synucleinopathy pathogenesis were identified, but only a few have reached the clinical stage [ 203 ].…”

Syntheses, reactivity, and biological applications of coumarins

“…The hallmark of PD consists of the presence of neuronal inclusions, called Lewi bodies, composed by phosphorylated and misfolded α-synuclein (α-syn) ( Gitto et al, 2022 ). The inhibition of α-syn aggregation represents a promising disease-modifying strategy to halt or slow PD-related neurodegeneration ( De Luca et al, 2022 ). In 2022, Kim and others reported the prevention of α-synuclein aggregation activity and the neuroprotective effect of the synthetic coumarin derivative PCiv ( 182 ) ( Figure 1B ) ( Kim et al, 2022 ).…”

Development of Small Molecules Targeting α-Synuclein Aggregation: A Promising Strategy to Treat Parkinson’s Disease

“…This HTS protocol seems biased to detect compounds targeting aggregated structures rather than monomeric proteins, which represents a clear advantage for its potential therapeutic use since they would only target pathological α-Syn assemblies without interfering with the activity of the soluble and functional protein. Interestingly, SC-D and ZPD-2 have been used as scaffolds to rationally design variants with enhanced activity or pharmacological properties [ 340 , 341 ]. More recently, SC-D and ZPD-2 chemical scaffolds were used to generate a library of 34 different compounds obtained through a similarity-based virtual screening filtered to contain exclusively molecules with good drug-like properties [ 342 ].…”