E. coli beta-galactosidase inhibitors through modifications at the aglyconic moiety: Experimental evidences of pyranose ring flexibility

LUIS CALLE; VIRGINIA ROLDÓS; F. JAVIER CAÑADA; MARÍA LAURA UHRIG; ALEJANDRO J. CAGNONI; VERÓNICA E. MANZANO; OSCAR VARELA; JESUS JIMÉNEZ-BARBERO

Chemistry - A European Journal

WILEY-VCH

Lugar: Weinheim; Año: 2013 vol. 19 p. 4262 - 4270

1521-3765

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 beta-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 phi or psi) 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.