5n6t

Publication Abstract from PubMed

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 beta-glucosidase inhibitors-we postulated that the corresponding carba "cyclopropyl" analogue would be a potent retaining beta-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 beta-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.

Carba-cyclophellitols Are Neutral Retaining-Glucosidase Inhibitors.,Beenakker TJM, Wander DPA, Offen WA, Artola M, Raich L, Ferraz MJ, Li KY, Houben JHPM, van Rijssel ER, Hansen T, van der Marel GA, Codee JDC, Aerts JMFG, Rovira C, Davies GJ, Overkleeft HS J Am Chem Soc. 2017 May 5. doi: 10.1021/jacs.7b01773. PMID:28463498^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.