title: Discovering benzamide derivatives as glycogen phosphorylase inhibitors and their binding site at the enzyme.
abstract: A series of novel benzamide derivatives was designed, synthesized, and their inhibitory activities against glycogen phosphorylase (GP) in the direction of glycogen synthesis by the release of phosphate from glucose-1-phosphate were evaluated. The structure-activity relationships (SAR) of these compounds are also presented. Within this series of compounds, 4m is the most potent GPa inhibitor (IC(50)=2.68 microM), which is nearly 100 times more potent than the initial compound 1. Analysis of mapping between pharmacophores of different binding sites and each compound demonstrated that these benzamide derivatives bind at the dimer interface of the rabbit muscle enzyme, and possible docking modes of compound 4m were explored by molecular docking simulation.
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, PR China.
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.forename: Honglin
authors.initials: H
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Luyong
authors.initials: L
authors.lastname: Zhang
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D018482:Muscle, Skeletal / Q000201:enzymology; D011487:Protein Conformation; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: C525229:2-amino-N-(3-aminophenyl)-4-fluoro-5-(1-methyl-1H-imidazol-2-ylthio)benzamide; D001549:Benzamides; D004791:Enzyme Inhibitors; D007093:Imidazoles; D024981:Glycogen Phosphorylase