Escherichia coli β‐Galactosidase Inhibitors through Modifications at the Aglyconic Moiety: Experimental Evidence of Conformational Distortion in the Molecular Recognition Process |
| |
Authors: | Luis Calle Dr Virginia Roldós Prof Dr F Javier Cañada María Laura Uhrig Alejandro J Cagnoni Verónica E Manzano Oscar Varela Prof Dr Jesus Jiménez‐Barbero |
| |
Institution: | 1. Chemical and Physical Biology, Centro de Investigationes Biològicas, CSIC, Ramiro de Maetzu 9, 28040 Madrid (Spain), Fax: (+34)?915‐360‐432;2. CIHIDECAR‐CONICET, Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, 1428 Buenos Aires (Argentina) |
| |
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. |
| |
Keywords: | conformation analysis enzyme models glycosides NMR spectroscopy S ligands |
|
|