title: Escherichia coli β-galactosidase inhibitors through modifications at the aglyconic moiety: experimental evidence of conformational distortion in the molecular recognition process.
abstract: Herein, we describe the use of thioglycosides as glycosidase inhibitors by employing novel modifications at the reducing end of these glycomimetics. The inhibitors display a basic galactopyranosyl unit (1→4)-bonded to a 3-deoxy-4-thiopentopyranose moiety. The molecular basis of the observed inhibition has been studied by using a combination of NMR spectroscopy and molecular modeling techniques. It is demonstrated that these molecules are not recognized by Escherichia coli β-galactosidase in their ground-state conformation, with a conformational selection process taking place. In fact, the observed conformational distortion depends on the chemical nature of the compounds and results from the rotation around the glycosidic linkage (variation of Φ or Ψ) or from the deformation of the six-membered ring of the pentopyranose. The bound conformations of the ligand are adapted in the enzymatic pocket with a variety of hydrogen-bond, van der Waals, and stacking interactions.
authors: Chemical and Physical Biology, Centro de Investigationes Biològicas, CSIC, Ramiro de Maetzu 9, 28040 Madrid, Spain.
authors: Luis
authors: L
authors: Calle
authors: Virginia
authors: V
authors: Roldós
authors: F Javier
authors: FJ
authors: Cañada
authors: María Laura
authors: ML
authors: Uhrig
authors: Alejandro J
authors: AJ
authors: Cagnoni
authors: Verónica E
authors: VE
authors: Manzano
authors: Oscar
authors: O
authors: Varela
authors: Jesus
authors: J
authors: Jiménez-Barbero
mesh_terms: D004187:Disaccharides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D013863:Thioglucosides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001616:beta-Galactosidase / Q000037:antagonists & inhibitors*
chemical_list: D004187:Disaccharides; D008024:Ligands; D013863:Thioglucosides; C582969:benzyl-3-deoxy-4-S-(beta-D-galactopyranosyl)-4-thio-beta-D-erythro-pentopyranoside; C582968:benzyl-3-deoxy-4-S-(beta-D-galactopyranosyl)-4-thio-beta-D-threo-pentopyranoside; D001616:beta-Galactosidase