Intramolecular carbohydrate-aromatic interactions and intermolecular van der Waals interactions enhance the molecular recognition ability of GMI glycomimetics for cholera toxin

The design and synthesis of two GM1 glycomimetics, 6 and 7, and analysis of their conformation in the free state and when complexed to cholera toxin is described. These compounds, which include an (R)-cyclohexyllactic acid and an (R)-phenyllactic acid fragment, respectively, display significant affinity for cholera toxin. A detailed NMR spectroscopy study of the toxin/glycomimetic complexes, assisted by molecular modeling techniques, has allowed their interactions with the toxin to be explained at the atomic level. It is shown that intramolecular van der Waals and CH-alpha carbohydrate-aromatic interactions define the conformational properties of 7, which adopts a three-dimensional structure significantly preorganized for proper interaction with the toxin. The exploitation of this kind of sugar-aromatic interaction, which is very well described in the context of carbohydrate/protein complexes, may open new avenues for the rational design of sugar mimics.