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

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 beta-aggregation through thioflavine T rather than 1b. Since compound 1 was most active, we determined the interaction between alpha-synuclein and 1 at 50 mu M (Kd) through microscale thermophoresis. Also, we observed differences in height and diameter of aggregates, and alpha-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 alpha-synuclein fibrils using molecular modelling. Docking experiments suggest that 1 preferably interact with the site 2 of alpha-synuclein through hydrogen bonds with residues Y39 and T44.

Automated summary

The study found that compounds 1 and 1a inhibit beta-aggregation of alpha-synuclein, while 1b does not. Additionally, the interaction between compound 1 and alpha-synuclein affects the morphology of aggregates, and prevents their impact on neurite outgrowth in nerve cells.