Glucose-based spiro-isoxazolines: A new family of potent glycogen phosphorylase inhibitors
Ημερομηνία
2009Συγγραφέας
Benltifa, MahmoudHayes, Joseph M.
Vidal, Sébastien
Gueyrard, David
Goekjian, Peter G.
Praly, Jean Pierre
Kizilis, Gregory
Tiraidis, Costas
Alexacou, Kyra Melinda
Chrysina, Evangelia D.
Zographos, Spyros E.
Leonidas, Demetres D.
Archontis, Georgios Z.
Oikonomakos, Nikos G.
Source
Bioorganic and Medicinal ChemistryVolume
17Issue
20Pages
7368-7380Google Scholar check
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Εμφάνιση πλήρους εγγραφήςΕπιτομή
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 Ki values ranging from 0.63 to 92.5 μM. 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. © 2009 Elsevier Ltd. All rights reserved.
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