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.

•Synthetic flavonoids synthesized based on QM/MM-PBSA binding free energy predictions.•Three compounds revealed as more potent than any natural flavonoid GP inhibitor.•Binding is synergistic with glucose and could be regulated by blood glucose levels.•Compound 43 an effective inhibitor of glycogenolysis in hepatocytes (IC50 = 70 µM).•X-ray crystallography studied the interactions responsible for the observed potencies.