Glucose-based spiro-isoxazolines: A new family of potent glycogen phosphorylase inhibitors

Benltifa, M.; Alexacou, K.-M.; Hayes, J. M.; Archontis, G.; Kizilis, G.; Goekjian, P. G.; Oikonomakos, N. G.; Gueyrard, D.; Praly, J.-P.; Vidal, S.; Zographos, S. E.; Chrysina, E. D.; Leonidas, D. D.; Tiraidis, C.

doi:10.1016/j.bmc.2009.08.060

Journal Article

PHPPUBDB-11918

Glucose-based spiro-isoxazolines: A new family of potent glycogen phosphorylase inhibitors

Benltifa, M. ; Hayes, J. M. ; Vidal, S. ; Gueyrard, D. ; Goekjian, P. G. ; Praly, J.-P. (Corresponding author) ; Kizilis, G. ; Tiraidis, C. ; Alexacou, K.-M. ; Chrysina, E. D.Extern* ; Zographos, S. E. ; Leonidas, D. D. ; Archontis, G. ; Oikonomakos, N. G. ; DESY

2009
Elsevier Amsterdam [u.a.]

Bioorganic & medicinal chemistry 17, 7368-7380 (2009) [10.1016/j.bmc.2009.08.060]

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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.

Keyword(s): Crystallography, X-Ray (MeSH) ; Enzyme Inhibitors: chemistry (MeSH) ; Enzyme Inhibitors: pharmacology (MeSH) ; Glucose: chemistry (MeSH) ; Glycogen Phosphorylase: antagonists & inhibitors (MeSH) ; Glycogen Phosphorylase: metabolism (MeSH) ; Kinetics (MeSH) ; Magnetic Resonance Spectroscopy (MeSH) ; Models, Molecular (MeSH) ; Oxazoles: chemistry (MeSH) ; Oxazoles: pharmacology (MeSH) ; Spectrometry, Mass, Electrospray Ionization (MeSH) ; Enzyme Inhibitors ; Oxazoles ; Glucose ; Glycogen Phosphorylase