The conformational behavior of novel glycosidase inhibitors with substituted azepan structures: An NMR and modeling study
The conformational analysis of a series of configurational isomers of 2-(hydroxymethyl)azepan-3,4,5,6-tetrols 1-4 has been carried out. H-1 NMR spectroscopic data, especially vicinal J couplings and nuclear Overhauser enhancements (NOE), assisted by molecular mechanics, molecular dynamics and Monte Carlo calculations, have been used. A fairly good agreement between experimental and calculated data has been found. The different isomers exist in a conformational equilibrium between two chair-like structures. TR-NOE experiments have also allowed us to demonstrate that the bound conformation of compound 2 to the beta-glucosidase from almonds is the major one of this compound present in solution. Finally, molecular docking of the different conformations of these compounds in the binding site of three different enzymes has been performed in order to try to rationalize the observed inhibition of these molecules. (C) Wiley-VCH Verlag GmbH Co.
WOS:000224697100004
2004
20
4119
4129
CSIC, Ctr Invest Biol, E-28040 Madrid, Spain. Ecole Normale Super, UMR 8642, Dept Chim, F-75231 Paris 05, France. Swiss Fed Inst Technol, EPFL, BCH, Inst Glychochem & Asymmetr Synth, CH-1015 Lausanne, Switzerland.
REVIEWED
EPFL