Conformational Study of Glycal-Type Neuraminidase Inhibitors

Abstract

The conformational flexibility of two glycal-type neuraminidase inhibitors has been studied, using several molecular modeling techniques. In agreement with the experimental data available, an intramolecular hydrogen bond, representing a key structural feature that controls the conformer distribution in solution, has been identified. The contribution of each substituent to the overall equilibrium was evaluated using simplified derivatives. Additionally, four methods for estimating NMR coupling constants from dihedral angles were evaluated and the Haasnoot method was found to be appropriate for this class of sugars. These results should allow a better understanding of the structural parameters governing physico-chemical properties of glycal-like compounds. Supplemental materials are available for this article. Go to the publisher's online edition of Journal of Carbohydrate Chemistry to view the free supplemental file.

Keywords:

• Molecular modeling
• Quantum chemistry
• Molecular dynamics
• Conformational analysis
• Neuraminidase inhibitors

ACKNOWLEDGEMENTS

This work was funded in part by the French Agency for Research (grant no. ANR-2010-BLAN-708-1). We thank Professor Jean-Yves Lallemand and the Institut de Chimie des Substances Naturelles for a research fellowship (to G.S.).

This work was presented in part (S.N.) at the European Young Investigators Workshop on “Carbohydrate Chemistry: From Synthesis to Applications” in Lyon, France, May 11–15, 2011.