Journal
FOOD AND CHEMICAL TOXICOLOGY
Volume 61, Issue -, Pages 14-27Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.fct.2012.12.030
Keywords
Glycogen phosphorylase; Type 2 diabetes; Flavonoids; Chrysin; Flavopiridol; Quercetagetin
Categories
Funding
- EU Marie Curie Early Stage Training (EST) [MEST-CT-020575]
- Marie Curie Host Fellowships for the Transfer of Knowledge (ToK) [MTKD-CT-2006-042776]
- Excellence in Research Institutes Greek General Secretariat for Research and Technology (2nd cycle), Ministry of Development
- EU [GA-230146, GA-245866]
- European Commission
- Department of Biochemistry and Biotechnology, University of Thessaly
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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 angstrom resolution. Chrysin is accommodated at the inhibitor site intercalating between the aromatic side chains of Phe285 and Tyr613 through pi-stacking interactions. Chrysin binds to GPb similar to 15 times weaker (K-i = 19.01 mu M) than flavopiridol (K-i = 1.24 mu M), 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 pi-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. (C) 2012 Elsevier Ltd. All rights reserved.
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