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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Tsitsanou, Katerina E. Hayes, Joseph M. Keramioti, Maria Mamais, Michalis Oikonomakos, Nikos G. Kato, Atsushi Leonidas, Demetres D. Zographos, Spyros E. |
| Description | Country affiliation: Greece Author Affiliation: Tsitsanou KE ( Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, Athens 11635, Greece.) |
| Abstract | Flavonoids have been discovered as novel inhibitors of glycogen phosphorylase (GP), a target to control hyperglycemia in type 2 diabetes. To elucidate the mechanism of inhibition, we have determined the crystal structure of the GPb-chrysin complex at 1.9 Å resolution. Chrysin is accommodated at the inhibitor site intercalating between the aromatic side chains of Phe285 and Tyr613 through π-stacking interactions. Chrysin binds to GPb approximately 15 times weaker (Ki=19.01 µM) than flavopiridol (Ki=1.24 µM), exclusively at the inhibitor site, and both inhibitors display similar behavior with respect to AMP. To identify the source of flavopiridols' stronger affinity, molecular docking with Glide and postdocking binding free energy calculations using QM/MM-PBSA have been performed and compared. Whereas docking failed to correctly rank inhibitor binding conformations, the QM/MM-PBSA method employing M06-2X/6-31+G to model the π-stacking interactions correctly reproduced the experimental results. Flavopiridols' greater binding affinity is sourced to favorable interactions of the cationic 4-hydroxypiperidin-1-yl substituent with GPb, with desolvation effects limited by the substituent conformation adopted in the crystallographic complex. Further successful predictions using QM/MM-PBSA for the flavonoid quercetagetin (which binds at the allosteric site) leads us to propose the methodology as a useful and inexpensive tool to predict flavonoid binding. |
| File Format | HTM / HTML |
| ISSN | 02786915 |
| Volume Number | 61 |
| e-ISSN | 18736351 |
| Journal | Food and Chemical Toxicology |
| Language | English |
| Publisher | Elsevier |
| Publisher Date | 2013-11-01 |
| Publisher Place | Great Britain (UK) |
| Access Restriction | One Nation One Subscription (ONOS) |
| Subject Keyword | Discipline Toxicology__semicolon__nutritional Discipline Sciences Enzyme Inhibitors Chemistry Pharmacology Flavonoids Metabolism Glycogen Phosphorylase Antagonists & Inhibitors Molecular Docking Simulation Methods Piperidines Adenosine Monophosphate Animals Binding Sites Binding, Competitive Chromones Crystallography, X-ray Kinetics Models, Molecular Protein Conformation Rabbits Structure-activity Relationship Comparative Study Journal Article Research Support, Non-u.s. Gov't |
| Content Type | Text |
| Resource Type | Article |
| Subject | Medicine Toxicology Food Science |
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