This research aims to improve the potential to treat Parkinson's disease (PD) by using active molecules. Various small molecules that produce desired effects have been shown to bind to alpha-synuclein oligomers or fibrils, misfolded proteins that are hallmarks of the disease. Through detailed knowledge about the nature and location of drug binding sites, the design of better drugs becomes possible.
Initially, we will screen for the most suitable drug candidates from a range of molecules with demonstrated activity using solution-state nuclear magnetic resonance (NMR) spectroscopy (technique used to study the physical and chemical properties of molecules). We will then define conditions under which we can employ solid-state NMR spectroscopy. With this technique, we will characterize the binding of a small-molecule compound to alpha-synuclein fibrils. Using methods that allow us to transfer magnetization from compound to fibril, we hope to assess the distance between the two with atomic detail, enabling us to understand how, where exactly and with what orientation the drug binds to the fibrils.
Relevance to Diagnosis/Treatment of Parkinson's Disease:
With a detailed understanding of the nature and location of drug binding sites in alpha-synuclein fibrils, biological chemists and computational biologists will be able to design better small-molecule compounds for future treatment of Parkinson's. These drugs may interact more specifically and more stably with the fibrils, which would increase their activity and reduce side effects of treatment.
This study is expected to enable design of tailored chemical compounds against Parkinson's in successive research. These improved drugs will be an important element of improved medical treatment against the symptoms and progress of the disease.