Carba-cyclophellitols are neutral retaining-glucosidase inhibitors

DOI: 10.1021/jacs.7b01773

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.

Journal Keywords: Peptides and proteins; Crystal structure; Inhibitors; Inhibition; Conformation

Subject Areas: Chemistry, Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography

Other Facilities: European Synchrotron Radiation Facility

Added On: 08/05/2017 09:54

Documents:
jacs.pdf

Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)