Researchers present a novel approach to identifying molecules associated with the progression of Parkinson disease and other neurodegenerative diseases.
When it comes to tracking the progression of Parkinson disease (PD), there are a myriad of biomarkers considered. Chiefly, the formation of alpha-synuclein (α-synuclein), an abnormal protein suggested to have a central role in the pathogenesis of PD, has emerged as a potential way of tracking the disease.
However, researchers of a study published in the journal Chemical Science noted that although the protein was identified more than 20 years ago, a reliable way to track α-synuclein, as well as other protein aggregates in the brain, has yet to be developed.
To make a viable mechanism to track α-synuclein, the accompanying press release highlights the need for new tracers, which are radioactive molecules that clinicians use to image tissues and organs for positron emission tomography (PET). Working for several years with the Michael J. Fox Foundation for Parkinson Research, researchers constructed an α-synuclein tracer, but it could not be implemented without data on the protein’s structure.
After the first publication of α-synuclein's structure and an increase in tools available from the field of computational chemistry, researchers began to develop their α-synuclein PET tracer. Utilizing a high-throughput computational method, researchers screened millions of candidate molecules to assess which 1 would bind to the known binding sites of α-synuclein.
Their approach is the first to identify an “exemplar,” a pseudo-molecule that fits perfectly into the binding site of α-synuclein. Building off this discovery, researchers then compared this exemplar with actual molecules that are commercially available to see which ones have a similar structure.
In their findings, a small subset of 20 promising candidates, derived from an initial pool of 7 million compounds, were screened, with 2 resulting compounds shown to have an extremely high binding affinity to α-synuclein.
Now provided with a large multi-institutional grant, researchers will now leverage these findings to develop PET tracers for PD and other neurodegenerative diseases. "I really see this as being a game changer on how we do PET probe development," said study author Robert Mach, PhD, Britton Chance Professor of Radiology. "The significance is that we're able to screen millions of compounds within a very short period of time, and we're able to identify large numbers of compounds that will likely bind with high affinity to alpha-synuclein. We're also going to apply this same method to the development of other probes that are important but have presented challenges to the field."
Ferrie JJ, Lengyel-Zhand Z, Janssen B, et al. Identification of a nanomolar affinity α-synuclein fibril imaging probe by ultra-high throughput in silico screening. Chem Sci. Published online September 10, 2020. doi:10.1039/D0SC02159H