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

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.

Network Pharmacology and Molecular Docking Analysis on Mechanisms of Isobavachalcone in Parkinson’s Disease

“…As shown in Figure 7B, ISO mainly interacted with the NAC region of α-synuclein through forming two hydrogen bonds with Glu61 and Gly73. Our result was in well consistent with that of Vittorio et al, who identified that amyloid fibril inhibitors targeting to α-synuclein bind in the sites located between the N-terminal and the NAC domains of the protein [14]. Therefore, we assume that αsynuclein is the putative target of ISO that can be directly bound by ISO in PD.…”

“…The chemical structure of ISO (CID: 5281255) was prepared from PubChem (https://pubchem.ncbi.nlm.nih.gov/) and converted into PDB format through OpenBabel3.1.1 [12]. A grid box with dimension of 126 × 126 × 126 Å3 and centre x = 97.487, y = 148.695 and z = −34,111, was set for molecular docking using AutoDock Tools (ADT, version 4.2.6) [13,14], and PyMOL software (https://pymol.org) was applied for and visualization.…”

“…According to the similar study of Vittorio et al [14], we defined the same region as the search space for the docking simulation. The docking results showed 10 protein-ligand binding conformations with binding energy < 0 kcal/mol (Figure 7A).…”

Discovery of Neuroprotective Agents Based on a 5-(4-Pyridinyl)-1,2,4-triazole Scaffold

“…The impacts of compounds 14 and 15 are similar to that of C-5 (21%). 22 The discrepancy between the influence of compounds 12 and 13 in Th-T and light-scattering signals suggests that the aggregates formed in the presence of these molecules exhibit a higher affinity for Th-T, likely being richer in intermolecular βsheet.…”

“…Accordingly, we focused our attention to identify of newer αsyn aggregation inhibitors oriented toward the NAC domain of α-syn. 22 From a set of 4-amino-5−(4-pyridinyl)-4H-1,2,4triazole-derived compounds, we identified the 3-(cinnamylsulfanyl)-5-(4-pyridinyl)-1,2,4-triazol-4-amine (11) that proved to reduce α-syn aggregation in an in vitro assay. Docking studies suggested the binding into a specific site placed between N-…”