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|Title:||N-(4-Substituted-benzoyl)-N '-(beta-D-glucopyranosyl)ureas as inhibitors of glycogen phosphorylase: Synthesis and evaluation by kinetic, crystallographic, and molecular modelling methods|
Chrysina, Evangelia D.
Kosmopoulou, Magda N.
Leonidas, Demetres D.
Zographos, Spyros E.
Oikonomakos, Nikos G.
|Type:||Journal Article (Scientific Journal article)|
|Abstract:||N-(4-Substituted-benzoyl)-N'-(beta-D-glucopyranosyl)ureas (substituents: Me, Ph, Cl, OH, OMe, NO2, NH2, COOH, and COOMe) were synthesised by ZnCl2 catalysed acylation of O-peracetylated beta-D-glucopyranosyl urea as well as in reactions of O-peracetylated or O-unprotected glucopyranosylamines and acyl-isocyanates. O-deprotections were carried out by base or acid catalysed transesterifications where necessary. Kinetic studies revealed that most of these compounds were low micromolar inhibitors of rabbit muscle glycogen phosphorylase b (RMGPb). The best inhibitor was the 4-methylbenzoyl compound (K-i = 2.3 mu M). Crystallographic analyses of complexes of several of the compounds with RMGPb showed that the analogues exploited, together with water molecules, the available space at the beta-pocket subsite and induced a more extended shift of the 280s loop compared to RMGPb in complex with the unsubstituted benzoyl urea. The results suggest the key role of the water molecules in ligand binding and structure-based ligand design. Molecular docking study of selected inhibitors was done to show the ability of the binding affinity prediction. The binding affinity of the highest scored docked poses was calculated and correlated with experimentally measured K-i values. Results show that correlation is high with the R-squared (R-2) coefficient over 0.9.|
|Journal Title:||Bioorganic & Medicinal Chemistry|
|Subject Category:||Science::Biology (General)|
Medicine::Pharmacy and materia medica
|Keywords:||N-Acyl-N '-beta-D-glucopyranosyl ureas; Glycogen phosphorylase; Inhibitor; X-ray crystallography; Molecular docking; Chemistry, Medicinal|
|Other Identifiers:||DOI: http://dx.doi.org/10.1016/j.bmc.2011.12.059|
|Journal web Location :||http://www.elsevier.com/locate/bmc|
|Rights holder:||© 2012 Elsevier Ltd. All rights reserved.|