Computational Design of Inhibitors of the Glycogenolysis Pathway as Potential Treatment for Type II Diabetes

Separate studies for type 1 diabetes (Diabetes Control & Complication Trial, 1993) and type 2 diabetes (UK Prospective Diabetes Study, 1998) have concluded that the longer term complications of diabetes such as cardiovascular diseases, neuropathies, nephropathies, retinopathies or hypertension could be prevented if blood glucose levels can be controlled.

Current pharmacological therapies for type 2 diabetes have limited efficacy in this regard, while the sometimes severe side-effects also associated with these medications necessitate the need for new and safer drugs.

Phosphorylase kinase(PhK) and glycogen phosphorylase (GP) have a direct effect on blood glucose levels via the glycogenolysis pathway. By regulating their activity, therefore, one has the potential to control glucose levels in type 2 diabetic patients.

This project focusses on the computational design of new and better inhibitors of PhK and GP, with the predictions validated experimentally in a multidisciplinary approach to drug design. The experimental work (synthesis, X-ray crystallography and biochemical assessment) involves several collaborations throughout Europe.

Project Lead: Dr. Joseph M. Hayes