2ati

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spinqualitylabelsall models 2ati, resolution 1.9Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Glycogen Phosphorylase Inhibitors

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

Using a focused screening approach, acyl ureas have been discovered as a, new class of inhibitors of human liver glycogen phosphorylase (hlGPa). The, X-ray structure of screening hit 1 (IC50 = 2 microM) in a complex with, rabbit muscle glycogen phosphorylase b reveals that 1 binds at the AMP, site, the main allosteric effector site of the dimeric enzyme. A first, cycle of chemical optimization supported by X-ray structural data yielded, derivative 21, which inhibited hlGPa with an IC50 of 23 +/- 1 nM, but, showed only moderate cellular activity in isolated rat hepatocytes (IC50 =, 6.2 microM). Further optimization was guided by (i) a 3D pharmacophore, model that was derived from a training set of 24 compounds and revealed, the key chemical features for the biological activity and (ii) the 1.9, angstroms crystal structure of 21 in complex with hlGPa. A second set of, compounds was synthesized and led to 42 with improved cellular activity, (hlGPa IC50 = 53 +/- 1 nM; hepatocyte IC50 = 380 nM). Administration of 42, to anaesthetized Wistar rats caused a significant reduction of the, glucagon-induced hyperglycemic peak. These findings are consistent with, the inhibition of hepatic glycogenolysis and support the use of acyl ureas, for the treatment of type 2 diabetes.

Disease

Known disease associated with this structure: Glycogen storage disease VI OMIM:[232700]

About this Structure

2ATI is a Single protein structure of sequence from Homo sapiens with GLC, IHU and PLP as ligands. Active as Phosphorylase, with EC number 2.4.1.1 Full crystallographic information is available from OCA.

Reference

Acyl ureas as human liver glycogen phosphorylase inhibitors for the treatment of type 2 diabetes., Klabunde T, Wendt KU, Kadereit D, Brachvogel V, Burger HJ, Herling AW, Oikonomakos NG, Kosmopoulou MN, Schmoll D, Sarubbi E, von Roedern E, Schonafinger K, Defossa E, J Med Chem. 2005 Oct 6;48(20):6178-93. PMID:16190745

Page seeded by OCA on Mon Nov 12 20:54:37 2007