Zero to 60 Drugs in Three Seconds – Finding New Uses for Existing Drugs to Treat Parkinson’s Disease

Can Translator be used to repurpose known drugs to treat symptoms of Parkinson’s disease?

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Parkinson's disease (PD) is a neurodegenerative disorder that affects predominantly dopamine-producing neurons in a specific area of the brain called the “substantia nigra.” Symptoms generally develop slowly over the years and include the following:

  • Tremors
  • Impaired posture/balance
  • Bradykinesia, apraxia
  • Anxiety/depression
  • Nausea
  • Gastroparesis

Many drug treatments are currently known, including:

  • Carbidopa/Levadopa inhibit dopamine metabolism in peripheral tissues.
  • Catechol-O-methyltransferase (COMT) inhibitors such as entacapone and tolcapone inhibit dopamine catabolism.
  • Monoamine oxidase-B (MAO-B) inhibitors such as selegiline and rasagiline inhibit dopamine catabolism.
  • Peripheral dopamine receptor blockers

How Might Translator Help?

Clinicians have the option to use currently approved drugs off-label to treat patients, but this requires a deep, up-to-date knowledge of the literature, which can be prohibitive for many physicians. Current databases that contain this information include data in very disparate formats, which can cause difficulty when attempting to integrate results cohesively.

Could Translator help physicians recognize specific drugs that target protein variants linked with Parkinson’s Disease to find potential new treatment options to be investigated, without creating undue burden on their time?

A promising new direction for PD research

Translator created a ranked list using connections found by linking data sources using Translator’s reasoning tools. The novel drugs identified were reviewed by researchers in the context of PD.

Among these results, a novel association between PD and the drug cilnidipine was discovered, connected through the action of alpha-synuclein (SYUA), a protein known to be important in presynaptic signaling. Cilnidipine is a dihydropyridine L- and N-type calcium-channel blocker, which is used as an antihypertension agent in Japan, China, India, Korea and some European countries.

Interestingly, a retrospective clinical records study suggests that the use of similar calcium channel blockers may be protective against PD; researchers speculate that dihydropyridine use may relieve chronic oxidative stress on dopaminergic neurons. This connection between PD and cilnidipine represents a promising new direction for preclinical research into the disease.

The Power of Translator

Identifying drugs that can be repurposed to treat complex disorders
Translator was used to find novel uses for drugs approved for other uses that may warrant further study as treatments for the symptoms of PD.

Mining across multiple disparate datasets
Translator found connections between information in several databases that have very different data formats and can be difficult to integrate.

Process Details:

The RTX reasoner returned the following knowledge graph: Parkinson’s Disease is connected to SYUA protein with the predicate 'gene associated to disease', SYUA is connected to cilnidipine with the predicate 'physically interacts', cilnidipine is connected to CACNA1B gene with the predicate 'targets', and CACNA1B is connected to calcium ion with the predicate 'regulates'.
Figure 1: The RTX reasoner returned a graph which connects Parkinson’s disease to the drug cilnidipine through its interaction with the protein SYUA, encoded by the gene SNCA. Since studies have suggested that calcium channel blockers may be protective for Parkinson’s symptoms, the graph also includes a a connection between cilnidipine and calcium through the action of CACNA1B, which is targeted by cilnidipine.


Ranking and Scoring

The ranked list of results that returned an association between PD and cilnidipine through the SYUA protein was generated by finding all of the proteins connected to the disease, then all of the drugs connected to those proteins, and sorting the resulting drug set by a measure of how many proteins are connected to both the drug and PD, using a Jaccard index. This results in drugs with many protein targets that are not associated with PD being given less weight, while drugs that have very few specific targets that are relevant to PD are given more weight.


The Vision of Translator

The Vision of Translator

Utilizing Open Clinical Data to Predict Patient Outcomes

Utilizing Open Clinical Data to Predict Patient Outcomes

Finding Marketed Drugs that might Treat an Unknown Syndrome by Perturbing the Disease Mechanism Pathway

Finding Marketed Drugs that might Treat an Unknown Syndrome by Perturbing the Disease Mechanism Pathway