Glucose-based spiro-isoxazolines: a new family of potent glycogen phosphorylase inhibitors.
Bioorg Med Chem
; 17(20): 7368-80, 2009 Oct 15.
Article
en En
| MEDLINE
| ID: mdl-19781947
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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Oxazoles
/
Glucógeno Fosforilasa
/
Inhibidores Enzimáticos
/
Glucosa
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Bioorg Med Chem
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2009
Tipo del documento:
Article
País de afiliación:
Francia