2QRQ

Glycogen Phosphorylase b in complex with (1R)-3'-(4-methylphenyl)-spiro[1,5-anhydro-D-glucitol-1,5'-isoxazoline]

Summary for 2QRQ

• Entry DOI: 10.2210/pdb2qrq/pdb
• Related: 2QRM 2QRP
• Descriptor: Glycogen phosphorylase, muscle form, (3S,5R,7R,8S,9S,10R)-7-(hydroxymethyl)-3-(4-methylphenyl)-1,6-dioxa-2-azaspiro[4.5]decane-8,9,10-triol, DIMETHYL SULFOXIDE, ... (4 entities in total)
• Functional Keywords: glycogenolysis, type 2 diabetes, acetylation, allosteric enzyme, carbohydrate metabolism, glycogen metabolism, glycosyltransferase, nucleotide-binding, phosphorylation, pyridoxal phosphate, transferase
• Biological source: Oryctolagus cuniculus (rabbit)
• Total number of polymer chains: 1
• Total formula weight: 99080.78

Authors

Gizilis, G.,Alexacou, K.M.,Chrysina, E.D.,Zographos, S.E.,Leonidas, D.D.,Oikonomakos, N.G. (deposition date: 2007-07-28, release date: 2008-07-29, Last modification date: 2024-04-03)

Primary citation

Benltifa, M.,Hayes, J.M.,Vidal, S.,Gueyrard, D.,Goekjian, P.G.,Praly, J.P.,Kizilis, G.,Tiraidis, C.,Alexacou, K.M.,Chrysina, E.D.,Zographos, S.E.,Leonidas, D.D.,Archontis, G.,Oikonomakos, N.G.
Glucose-based spiro-isoxazolines: a new family of potent glycogen phosphorylase inhibitors.
Bioorg.Med.Chem., 17:7368-7380, 2009

PubMed Abstract: A series of glucopyranosylidene-spiro-isoxazolines was prepared through regio- and stereoselective [3+2]-cycloaddition between the methylene acetylated exo-glucal and aromatic nitrile oxides. The deprotected cycloadducts were evaluated as inhibitors of muscle glycogen phosphorylase b. The carbohydrate-based family of five inhibitors displays K(i) values ranging from 0.63 to 92.5 microM. The X-ray structures of the enzyme-ligand complexes show that the inhibitors bind preferentially at the catalytic site of the enzyme retaining the less active T-state conformation. Docking calculations with GLIDE in extra-precision (XP) mode yielded excellent agreement with experiment, as judged by comparison of the predicted binding modes of the five ligands with the crystallographic conformations and the good correlation between the docking scores and the experimental free binding energies. Use of docking constraints on the well-defined positions of the glucopyranose moiety in the catalytic site and redocking of GLIDE-XP poses using electrostatic potential fit-determined ligand partial charges in quantum polarized ligand docking (QPLD) produced the best results in this regard.

PubMed: 19781947
DOI: 10.1016/j.bmc.2009.08.060

Experimental method

X-RAY DIFFRACTION (1.8 Å)