Dammarane triterpenes targeting α-synuclein: biological activity and evaluation of binding sites by molecular docking

• Published in: Journal of Enzyme Inhibition and Medicinal Chemistry
• Main Authors: Cornejo, Alberto, Caballero, Julio, Simirgiotis, Mario, Torres, Vanessa, Sánchez, Luisa, Díaz, Nicolás, Guimaraes, Marcela, Hernández, Marcos, Areche Medina, Carlos Alberto, Alfaro, Sergio, Caballero, Leonardo, Melo, Francisco
• Format: Article in Journal/Newspaper
• Language: English
• Published: Taylor & Francis Ltd. 2021
• Subjects: Parkinson’s disease; Oligomers; Drug targets; Natural compounds modifiers; Inach; antartic*; Instituto Antartico Chileno
• Online Access: https://doi.org/10.1080/14756366.2020.1851216; https://repositorio.uchile.cl/handle/2250/183621

Parkinson’s disease (PD) is a neurodegenerative disorder that affects adult people whose treatment is palliative. Thus, we decided to test three dammarane triterpenes 1, 1a, 1b, and we determined that 1 and 1a inhibit b-aggregation through thioflavine T rather than 1b. Since compound 1 was most active, we determined the interaction between a-synuclein and 1 at 50 mM (Kd) through microscale thermophoresis. Also, we observed differences in height and diameter of aggregates, and a-synuclein remains unfolded in the presence of 1. Also, aggregates treated with 1 do not provoke neurites’ retraction in N2a cells previously induced by retinoic acid. Finally, we studied the potential sites of interaction between 1 with a-synuclein fibrils using molecular modelling. Docking experiments suggest that 1 preferably interact with the site 2 of a-synuclein through hydrogen bonds with residues Y39 and T44. Instituto Antartico Chileno (INACH) RT_18-19 Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT) CONICYT FONDECYT 1170718 Mario Simirgiotis FONDECYT Regular 1180059 Francisco Melo FONDECYT Regular 1201013 Fondequip EQM130149 USA2055-042031MH_POSTDOC Versión publicada - versión final del editor