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Escherichia coli β‐Galactosidase Inhibitors through Modifications at the Aglyconic Moiety: Experimental Evidence of Conformational Distortion in the Molecular Recognition Process
Author(s) -
Calle Luis,
Roldós Virginia,
Cañada F. Javier,
Uhrig María Laura,
Cagi Alejandro J.,
Manzano Verónica E.,
Varela Oscar,
JiménezBarbero Jesus
Publication year - 2013
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201203673
Subject(s) - glycosidic bond , chemistry , moiety , hydrogen bond , stereochemistry , molecular model , van der waals force , molecular dynamics , molecule , helix (gastropod) , crystallography , glycoside hydrolase , nuclear magnetic resonance spectroscopy , computational chemistry , enzyme , biochemistry , organic chemistry , ecology , snail , biology
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.