Most molecules made by chemists are extremely small, much smaller than the size of cells or other biological machinery essential to life. My project aims to make structures out of these small molecules which are thousands of times larger and consequently have different and useful properties.

Receptors are proteins that are important features in cell signalling (a form of communication between cells). Sitting in the membrane of cells, they can pass on information from one cell to another. Amongst these, glutamate receptors play a significant role in our brain, as they are responsible for memory and learning. Furthermore, their malfunction is directly involved in neurodegenerative diseases such as Parkinson’s, Alzheimer’s and Huntington’s disease. The exact understanding of their function can help us to develop cures for these degenerative diseases.

The family of the glutamate receptors is very diverse and some of its members are already well understood. However, the subtype GluK2 – which is quite abundant in the brain – remains a mystery. It is believed to play a role in strokes, migraines and epilepsy, but not a lot is known about its exact function. This is mainly due to the lack of biochemical tools to study this receptor. Specific inhibitors, that bind to the receptor and block it, are necessary to study the function of the receptor.

My project involves the design and synthesis of specific inhibitors for GluK2. It is based on the natural product arctigenin, which has been isolated from plants like the greater burdock. Arctigenin has been found to bind to glutamate receptors weakly. I have used molecular modelling to study the interaction of the inhibitor with the protein and identify key features that are necessary for the binding and to design molecules that show a stronger, more specific binding to the GluK2 subtype.

During my PhD I am preparing a series of these molecules. In collaboration with colleagues from the Pharmacology and Physiology department, I will proceed to test their activity on GluK2 receptors. Based on these results further target molecules can be designed and synthesised as necessary.