Journal of the American Chemical Society
Journal of the American Chemical Society
5 years ago

Carba-cyclophellitols Are Neutral Retaining-Glucosidase Inhibitors

Carba-cyclophellitols Are Neutral Retaining-Glucosidase Inhibitors
Erwin R. van Rijssel, Judith H. P. M. Houben, Wendy A. Offen, Gijsbert A. van der Marel, Johannes M. F. G. Aerts, Kah-Yee Li, Dennis P. A. Wander, Lluís Raich, Carme Rovira, Marta Artola, Thomas Hansen, Thomas J. M. Beenakker, Jeroen D. C. Codée, Herman S. Overkleeft, Maria J. Ferraz, Gideon J. Davies
The conformational analysis of glycosidases affords a route to their specific inhibition through transition-state mimicry. Inspired by the rapid reaction rates of cyclophellitol and cyclophellitol aziridine—both covalent retaining β-glucosidase inhibitors—we postulated that the corresponding carba “cyclopropyl” analogue would be a potent retaining β-glucosidase inhibitor for those enzymes reacting through the 4H3 transition-state conformation. Ab initio metadynamics simulations of the conformational free energy landscape for the cyclopropyl inhibitors show a strong bias for the 4H3 conformation, and carba-cyclophellitol, with an N-(4-azidobutyl)carboxamide moiety, proved to be a potent inhibitor (Ki = 8.2 nM) of the Thermotoga maritima TmGH1 β-glucosidase. 3-D structural analysis and comparison with unreacted epoxides show that this compound indeed binds in the 4H3 conformation, suggesting that conformational strain induced through a cyclopropyl unit may add to the armory of tight-binding inhibitor designs.

Publisher URL: http://dx.doi.org/10.1021/jacs.7b01773

DOI: 10.1021/jacs.7b01773

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