2-deoxy-2-fluorohexoses as inhibitors of glycosyl hydrolases


M. Krupička, I. Tvaroška


Slovak Academy of Sciences, Institute of Chemistry, Dubravska cesta 9, Bratislava, Slovak Republic



Keywords: DFT, NBO, intermediate, stability



The 2-deoxy-2-fluorohexoses are known to act as inhibitors for glycosyl hydrolases and are widely used to obtain the crystal structure of enzyme with substrate. The question has been raised, whether the stabilization of reaction intermediate is result of enzyme-substrate interaction, or the substrate itself is stabilized and does not undergo further reaction steps.

The reaction was modeled as acid catalyzed hydrolysis, where the protonated intermediate and oxocarbenium ion were considered. The relative stability of these intermediates and the differences in charge distribution are discussed.  The properties of intermediates are calculated at B3LYP/6-311++G(d,p),  the enzymatic environment is omitted.

It was found that both reaction intermediates are less stable for the 2-deoxy-2-fluoro substrates. The energy difference is in order 6-8 kcal/mol, and this suggests two modes of action for the inhibitor, (i) higher barrier towards the protonation and (ii) electron-withdrawing properties of the fluorine atom destabilizing the oxocarbenium intermediate.


Acknowledgement: This work has been supported by MRTN-CT-2006-035866 (REVCAT) and VEGA 2/0176/09