Carba-cyclophellitols Are Neutral Retaining-Glucosidase Inhibitors.

ABSTRACT: 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 ?-glucosidase inhibitors-we postulated that the corresponding carba "cyclopropyl" analogue would be a potent retaining ?-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 (K_i = 8.2 nM) of the Thermotoga maritima TmGH1 ?-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.

SUBMITTER: Beenakker TJM 

PROVIDER: S-EPMC5437670 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature