6Y5O

The crystal structure of glycogen phosphorylase in complex with 20

Summary for 6Y5O

• Entry DOI: 10.2210/pdb6y5o/pdb
• Descriptor: Glycogen phosphorylase, muscle form, 2-(4-fluorophenyl)-5,7-bis(oxidanyl)chromen-4-one (3 entities in total)
• Functional Keywords: transferase, glycogen metabolism
• Biological source: Oryctolagus cuniculus (Rabbit)
• Total number of polymer chains: 1
• Total formula weight: 97791.55

Authors

Kyriakis, E.,Koulas, S.M.,Skamnaki, V.T.,Leonidas, D.D. (deposition date: 2020-02-25, release date: 2020-08-19)

Primary citation

Chetter, B.A.,Kyriakis, E.,Barr, D.,Karra, A.G.,Katsidou, E.,Koulas, S.M.,Skamnaki, V.T.,Snape, T.J.,Psarra, A.G.,Leonidas, D.D.,Hayes, J.M.
Synthetic flavonoid derivatives targeting the glycogen phosphorylase inhibitor site: QM/MM-PBSA motivated synthesis of substituted 5,7-dihydroxyflavones, crystallography, in vitro kinetics and ex-vivo cellular experiments reveal novel potent inhibitors.
Bioorg.Chem., 102:104003-104003, 2020

PubMed Abstract: Glycogen phosphorylase (GP) is an important target for the development of new anti-hyperglycaemic agents. Flavonoids are novel inhibitors of GP, but their mode of action is unspecific in terms of the GP binding sites involved. Towards design of synthetic flavonoid analogues acting specifically at the inhibitor site and to exploit the site's hydrophobic pocket, chrysin has been employed as a lead compound for the in silico screening of 1169 new analogues with different B ring substitutions. QM/MM-PBSA binding free energy calculations guided the final selection of eight compounds, subsequently synthesised using a Baker-Venkataraman rearrangement-cyclisation approach. Kinetics experiments against rabbit muscle GPa and GPb together with human liver GPa, revealed three of these compounds (11, 20 and 43) among the most potent that bind at the site (K s < 4 µM for all three isoforms), and more potent than previously reported natural flavonoid inhibitors. Multiple inhibition studies revealed binding exclusively at the inhibitor site. The binding is synergistic with glucose suggesting that inhibition could be regulated by blood glucose levels and would decrease as normoglycaemia is achieved. Compound 43 was an effective inhibitor of glycogenolysis in hepatocytes (IC = 70 µM), further promoting these compounds for optimization of their drug-like potential. X-ray crystallography studies revealed the B-ring interactions responsible for the observed potencies.

PubMed: 32771768
DOI: 10.1016/j.bioorg.2020.104003

Experimental method

X-RAY DIFFRACTION (2.33 Å)