Charge trumps shape: J Am Chem Soc paper for Williams Group
Sugar-derived heterocycles are widely used as glycosidase inhibitors owing to their ability to mimic the partial positive charge of the reaction transition state, and match the shape of the substrate.
However, the preference for shape versus charge mimicry for inhibition of a particular glycosidase needs to be determined on a case-by-case basis.
A collaboration between the group of Spencer Williams (University of Melbourne) and colleagues from Spain, France and the UK, has used an integrated synthetic, crystallographic and quantum mechanical approach to assess the contributions of shape and charge to inhibition of a glycosidase involved in degrading complex carbohydrates attached to proteins.
Neutral molecules designed to imitate the distorted shape of the transition state were less effective inhibitors than molecules that imitated the charge of the transition state but with poor shape mimickry.
This discovery inspired the design and synthesis of mannosyl-noeuromycin (ManNOE), the most potent inhibitor yet reported for this enzyme, which achieves its inhibition by optimizing polar and ionic interactions with the enzyme.
(Petricevic, M., Sobala, L.F., Fernandes, P.Z., Raich, L., Thompson, A.J., Bernardo-Seisdedos, G., Millet, O., Zhu, S., Sollogoub, M., Jiménez-Barbero, J., Rovira, C., Davies, G.J., Williams, S.J., J. Am. Chem. Soc., 2017, 139, 1089–1097).
Professor Spencer J Williams