The prototype of glycogen phosphorylase.

The quest for the discovery of new antihyperglycemic agents has been more intense the last years due to the rapid increase of mortality associated with type 2 diabetes. Glycogen metabolism has been one of the major causes of the elevated blood glucose levels; hence, special attention has been drawn to the control of the enzymes implicated in the relevant pathway. To this end, the allosteric enzyme of glycogen phosphorylase, has been proposed as molecular target for the design of potential new antidiabetic agents by an interdisciplinary approach comprising organic synthesis, kinetic and X-ray crystallographic studies and physiological experiments. The results derived from the thorough investigation of the catalytic site of the enzyme with the structure-based inhibitor design approach are summarized with emphasis on the most potent inhibitors identified for different classes of compounds.