Over the past month I have been exploring DistilBio to look at specific use cases that would be useful to someone working in the area of drug discovery. I came up with several interesting and encouraging results. In this post, the first in this series, I will show you how DistilBio can be used to search for the target of a drug.
The drug I have chosen is Sitagliptin (Trade Name: Januvia), an anti-diabetic drug developed and marketed by Merck & Co. Lets see what DistilBio tells me about this drug.
First, lets look at what is Sitagliptin and the associated disease indication.
Query: Sitagliptin > disease indication
Below, we can see the result..
We can see that Sitagliptin is a hypoglycemic/anti-diabetic drug. The next question that comes to mind is what are the protein targets of Sitagliptin? Lets also add a node to see the function of the protein targets.
Query: Sitagliptin > protein > function
and the result is
We can see 2 protein targets DPP4 and SO4C1, both in humans. (Uniprot Protein Identifiers are displayed in DistilBio). Highlighting the column for protein targets allows us to view information about the proteins.
The functions show us that DPP4 is a dipeptidyl peptidase enzyme that cleaves peptides to regulate their levels and also plays a role in T-cell activation.
SO4C1 is a transporter of pharmacological substances. So I am assuming that DPP4 is the primary protein target of Sitagliptin.
Now this is puzzling. What role does DPP4 play in diabetes or regulating blood glucose? Will proteins interacting with DPP4 give us this information? Lets also focus on protein interactions in humans.
Query: Sitagliptin > protein > protein > human
We get the following results..
We can see a list of proteins that interact with DPP4. But which of these are involved in blood glucose regulation?
The next step is to filter these to find the proteins that interact with DPP4 and also play a role in glucose level regulation. To do this, select the column with the interacting proteins and search for “glucose” in the field named ‘filter’.
That’s interesting. We get 2 proteins that interact with DPP4 – GIP and GLUC. Further exploration of the data for GIP and GLP-1 (a polypeptide product of Glucagon) indicate that these proteins play an important role in insulin secretion.
Bingo!! … Using DistilBio we were able to figure out that Sitagliptin, an anti-diabetic drug targets/inhibits the protein DPP4. DPP4 interacts with Gastric Inhibitory Protein (GIP) and Glucagon like peptide -1 (GLP-1). GIP and GLP-1 are potent stimulators of insulin and also suppress glucagon. Currently, DistilBio does not give us the explicit type of interaction (activation or inhibition) between DPP4 and GIP/GLP-1, but I am assuming that DPP4 inhibits GIP and GLP-1, therefore inhibiting DPP4 activates these 2 proteins. Types of interactions between proteins, genes, drugs etc., is a feature that will be available in DistilBio soon.
Here, I have shown the use of DistilBio to find the targets of a drug and its role in a disease indication. Similarly, you could use it to find common targets of drugs, drug interactions, protein interactions etc., which would be a useful tool for drug discovery.
Over the next several weeks, I will be exploring some more practical examples of how DistilBio could be used. Stay tuned for more use cases.
About the Author: Preethi is currently with Metaome as a Consultant Biologist. A post-graduate in Biochemistry and Bioinformatics, she has worked in Systems Biology and computational modeling of biological processes.