New Inhibitors of Glycogen Phosphorylase as Potential Antidiabetic Agents

• Published in: Current medicinal chemistry Vol. 15; no. 28; pp. 2933 - 2983
• Main Authors: SOMSHK, L, CZIFRHK, K, ZOGRAPHOS, S. E, OIKONOMAKOS, N. G, TOTH, M, BOKOR, E, CHRYSINA, E. D, ALEXACOU, K.-M, HAYES, J. M, TIRAIDIS, C, LAZOURA, E, LEONIDAS, D. D
• Format: Journal Article
• Language: English
• Published: Oak Park, IL Bentham Science Publishers Ltd 01.12.2008; Bentham
• Subjects: Allosteric Site; Animals; Binding Sites; Biological and medical sciences; Chemistry, Pharmaceutical - methods; Diabetes Mellitus, Type 2 - drug therapy; Drug Design; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; General and cellular metabolism. Vitamins; Glycogen Phosphorylase - antagonists & inhibitors; Glycogen Phosphorylase - chemistry; Humans; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Inhibitory Concentration 50; Ligands; Liver - enzymology; Medical sciences; Molecular Conformation; Pharmacology. Drug treatments; Protein Structure, Tertiary; Type 2 diabetes; structure-based drug design; Enzyme; Isozyme; Transferases; Glycosyltransferases; Enzyme inhibitor; Inhibitor enzyme complex; Review; antidiabetic agent; Modeling; Phosphorylase; Hypoglycemic agent; Structure activity relation; inhibitor; Glycogen phosphorylase; Molecular model; Hexosyltransferases
• ISSN: 0929-8673; 1875-533X
• DOI: 10.2174/092986708786848659

The protein glycogen phosphorylase has been linked to type 2 diabetes, indicating the importance of this target to human health. Hence, the search for potent and selective inhibitors of this enzyme, which may lead to antihyperglycaemic drugs, has received particular attention. Glycogen phosphorylase is a typical allosteric protein with five different ligand binding sites, thus offering multiple opportunities for modulation of enzyme activity. The present survey is focused on recent new molecules, potential inhibitors of the enzyme. The biological activity can be modified by these molecules through direct binding, allosteric effects or other structural changes. Progress in our understanding of the mechanism of action of these inhibitors has been made by the determination of high-resolution enzyme inhibitor structures (both muscle and liver). The knowledge of the three-dimensional structures of protein-ligand complexes allows analysis of how the ligands interact with the target and has the potential to facilitate structure-based drug design. In this review, the synthesis, structure determination and computational studies of the most recent inhibitors of glycogen phosphorylase at the different binding sites are presented and analyzed.