Creating Compounds to Treat Disease

graphical representation of compound 64 docked into SIRT2

Sirtuins are a group of seven compounds (SIRT1 - SIRT7) that are involved in a wide range of biological functions. Because of their role in gene regulation, researchers believe that sirtuin inhibitors may be useful as treatments for diseases. For example, drug designers believe that SIRT2 inhibition could be a useful treatment for Parkinson’s disease.

MSI Principal Investigator Liqiang Chen, an assistant professor in the Center for Drug Design in the Academic Health Center, and his colleagues recently published a paper discussing a method of creating SIRT2 inhibitors. The method uses fragments of other compounds that have characteristics that would be useful in the compound. The researchers combine the fragments in new ways, and then analyze their activity. One of these new compounds, dubbed “compound 64” by the researchers, showed particular promise as a SIRT2 inhibitor. It was also notable in that it was very selective in interacting with SIRT2 but not with its most similar sirtuins, SIRT1 or SIRT3.

Once the researchers had identified compound 64 as a likely candidate for further research, they used MSI resources to perform computational modeling to study how it attaches to SIRT2. While this research is preliminary, compound 64 shows promise as a possible treatment for the symptoms of Parkinson’s disease. Professor Chen and his colleagues are continuing their investigations into compound 64.

This research has been supported by the Center for Drug Design at the University of Minnesota. The group’s paper can be found on the Journal of Medicinal Chemistry website: Cui, Huaqing, Zeeshan Kamal, Teng Ai, Yanli Xu, Swati S. More, Daniel J. Wilson, and Liqiang Chen. 2014. Discovery of Potent and Selective Sirtuin 2 (SIRT2) Inhibitors Using a Fragment-Based Approach. Journal of Medicinal Chemistry 57 (20): 8340-57.

Image description: Potential binding modes and interactions of compound 64 docked into the crystal structure of SIRT2 (PDB entry 1j8f). (A) Two binding modes of compound 64 in the active site of SIRT2 (surface representation). (B) Potental interactions between compound 64 and SIRT2 in the first binding mode (magenta). (C) Potential interactions between compound 64 and SIRT2 in the second mode (green). Image and description, Cui, H. et al., J Med Chem 57 (20): 8340-57 (2014). ©2014 American Chemical Society.

posted on January 7, 2015

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