Abstract
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.
Keywords: Glycogen phosphorylase, inhibitor, type 2 diabetes, structure-based drug design, antidiabetic agent
Current Medicinal Chemistry
Title: New Inhibitors of Glycogen Phosphorylase as Potential Antidiabetic Agents
Volume: 15 Issue: 28
Author(s): L. Somsak, K. Czifrak, M. Toth, E. Bokor, E. D. Chrysina, K.-M. Alexacou, J. M. Hayes, C. Tiraidis, E. Lazoura, D. D. Leonidas, S. E. Zographos and N. G. Oikonomakos
Affiliation:
Keywords: Glycogen phosphorylase, inhibitor, type 2 diabetes, structure-based drug design, antidiabetic agent
Abstract: 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.
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Somsak L., Czifrak K., Toth M., Bokor E., Chrysina D. E., Alexacou K.-M., Hayes M. J., Tiraidis C., Lazoura E., Leonidas D. D., Zographos E. S. and Oikonomakos G. N., New Inhibitors of Glycogen Phosphorylase as Potential Antidiabetic Agents, Current Medicinal Chemistry 2008; 15 (28) . https://dx.doi.org/10.2174/092986708786848659
DOI https://dx.doi.org/10.2174/092986708786848659 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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