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Carba-cyclophellitols Are Neutral Retaining-Glucosidase Inhibitors

DOI: 10.1021/jacs.7b01773 DOI Help

Authors: Thomas J. M. Beenakker (Leiden University) , Dennis P. A. Wander (Leiden University) , Wendy Offen (University of York) , Marta Artola (Leiden University) , Lluís Raich (Universitat de Barcelona) , Maria J. Ferraz (Leiden University) , Kah-yee Li (Leiden University) , Judith H. P. M. Houben (Leiden University) , Erwin R. Van Rijssel (Leiden University) , Thomas Hansen (Leiden University) , Gijsbert A. Van Der Marel (Leiden University) , Jeroen D. C. Codée (Leiden University) , Johannes M. F. G. Aerts (Leiden University) , Carme Rovira (Universitat de Barcelona; Institució Catalana de Recerca i Estudis Avançats (ICREA)) , Gideon J. Davies (University of York) , Herman S. Overkleeft (Leiden University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of The American Chemical Society

State: Published (Approved)
Published: May 2017
Diamond Proposal Number(s): 13587

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 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.

Subject Areas: Chemistry


Instruments: I02-Macromolecular Crystallography

Other Facilities: European Synchrotron Radiation Facility