A novel structure-based drug discovery approach for phosphatase enzymes

Protein phosphatase enzymes have vital roles in many cellular processes and are implicated in a growing number of diseases including cancer, cardiovascular, neurological, immunological and metabolic diseases. Conventional laboratory-based drug discovery approaches have met with limited success in this enzyme family. New strategies to identify small molecules which modulate the function of these enzymes offer an exciting opportunity to unlock the therapeutic potential of this enzyme class. The project will adopt a novel drug discovery strategy utilising a unique set of computational tools and biophysical techniques to identify small molecule inhibitors at selected phosphatases. Following selection of appropriate phosphatase targets based on relevance to disease and availability of suitable 3D protein structures, a suite of ‘in silico’ computational tools will be used to mine 3D databases to identify molecules that will bind to ‘pockets’ on the enzymes. Biochemical techniques will then be used to produce the enzymes in the laboratory and various biophysical approaches will be used to measure binding of the novel molecules at the target phosphatase enzyme(s). Ultimately, the project will provide novel chemical starting points for optimisation which may then yield candidate drugs to treat human disease.