Recent Advances in the Allosteric Inhibition of Glycogen Phosphorylase

W.      A. Loughlin

doi:10.2174/1389557511009011139

Abstract

Glycogen Phosphorylase (GP) is an important target for the development of anti-hyperglycaemic drugs. GP is an enzyme which is moderated allosterically with multiple ligand binding sites where inhibitors can potentially modulate enzyme activity. The search for potent and isoform selective inhibitors of GP is ongoing with an increasing focus on allosteric inhibition. In this review, the structural diversity, and enzyme interactions of the most recent inhibitors, and in particular allosteric inhibitors, of GP at the different key binding sites are explored. A range of inhibitors of GP, with known as well as unknown binding site or mechanism is presented.

Keywords: Glycogen phosphorylase, allosteric inhibition, inhibitor, structure based drug design, anti-hyperglycaemic drugs, glycogen metabolism, blood glucose levels, glucose-1-phosphate, glycogenolysis, phosphorylation, human liver glycogen phosphorylase, human muscle glycogen phosphorylase, human brain glycogen phosphorylase, AMP-allosteric site, isoenzymes, purine site inhibitors, antitumour drugs, pyridoxal-5'-phosphate (PLP), phosphorylase kinase, dephosphorylation, protein phosphatase 1, glucose-6-phosphate, aspartic acid, phosphate recognition site, allosteric activator, allos-teric indole site, phosphate binding site, glycogen storage site, allosteric regulation, phosphorylation state, GP molecule, C-alkanoyl glycosides, Waals interactions, oleanolic acid, channel of GP, PURINE NUCLEOSIDE SITE INHIBITORS, flavopiridol, structure activity relation-ship, indirubin derivatives, van der Waals interac-tions, phenyl diacid, Bayer diacid, naphthalene moiety, pentacyclic triterpenoids maslinic acid, RMGPb-asiatic acid, OH group, 23-hydroxybetulinic acid derivatives, CP-320,626, CP-526,423, allosteric indole inhibitors, rHLGPa, chlorobenzamide, 3,4-dichlorophenyl moiety, 6-chloroindole moiety, Thieno[2,3-b]pyrroles, thieno[2,3-b]pyrrole group, hy-drophobic pocket, non-indole compounds, matched molecular pair analysis, benzamide derivatives, amide linker, heterocyclic scaffold, Heterocyclic amides, facile aminolysis reaction, 5-benzylidene-thiazolidine-2,4-diones, flavones, gallic acid, liver X receptor, thalidomide, glycogen-associated protein phosphatase 1, GlaxoSmithKline