The druggability of the ATP binding site of glycogen phosphorylase kinase probed by coumarin analogues

Glycogen phosphorylase kinase (PhK) converts by phosphorylation, the inactive glycogen (GPb) into active GPa in glycogenolytic pathway. It is a complex enzyme comprising of catalytic (?) and three regulatory subunits (?, ?, ?) forming hexadecamer with stoichiometry (????)4. Several studies have indicated PhK as promising target for development antihyperglycemics its inhibition blocks glycogenolysis liver potential therapeutic cancer against pathological angiogenesis tumor progression. The identification compounds that inhibit through their direct binding to site an effective approach identify bioactive molecules significance. Towards this, structure N-terminal domain (residues 1–298) ? subunit (PhK?trnc) has been determined X-ray crystallography while staurosporine indirubin analogues characterized potent inhibitors targeting ATP site. In this study, series 38 synthetic naturally occurring coumarins were screened PhK?trnc, vitro, using photometric assay. IC50 values two most PhK?trnc pharmacologically relevant target, human isoform (PHKG2A). Their cellular efficacy toxicity HepG2 cells further assessed ex vivo. Docking experiments structural comparison previously described reveal mode coumarin scaffold at no hinge region role conserved ?3-Lys binding. experimental findings provide insights implications drug design.