Glucose-based spiro-isoxazolines: a new family of potent glycogen phosphorylase inhibitors.
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.
Benltifa
Mahmoud
M
Université de Lyon, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires associé au CNRS, UMR 5246, Laboratoire de Chimie Organique 2, Bâtiment Curien, 43 Boulevard du 11 Novembre 1918, F-69622 Villeurbanne, France.
Hayes
Joseph M
JM
Vidal
Sébastien
S
Gueyrard
David
D
Goekjian
Peter G
PG
Praly
Jean-Pierre
JP
Kizilis
Gregory
G
Tiraidis
Costas
C
Alexacou
Kyra-Melinda
KM
Chrysina
Evangelia D
ED
Zographos
Spyros E
SE
Leonidas
Demetres D
DD
Archontis
Georgios
G
Oikonomakos
Nikos G
NG
D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005947:Glucose / Q000737:chemistry*; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010080:Oxazoles / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization
D004791:Enzyme Inhibitors; D010080:Oxazoles; D024981:Glycogen Phosphorylase; D005947:Glucose