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

作者: Ben A. Chetter , Efthimios Kyriakis , Daniel Barr , Aikaterini G. Karra , Elisabeth Katsidou

DOI: 10.1016/J.BIOORG.2020.104003

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摘要: Abstract Glycogen phosphorylase (GP) is an important target for the development of new anti-hyperglycaemic agents. Flavonoids are novel inhibitors GP, but their mode action unspecific in terms GP binding sites involved. Towards design synthetic flavonoid analogues acting specifically at inhibitor site and to exploit site’s hydrophobic pocket, chrysin has been employed as a lead compound silico screening 1169 with different B ring substitutions. QM/MM-PBSA free energy calculations guided final selection eight compounds, subsequently synthesised using Baker-Venkataraman rearrangement-cyclisation approach. Kinetics experiments against rabbit muscle GPa GPb together human liver GPa, revealed three these compounds (11, 20 43) among most potent that bind (Ki s

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