Screening-based discovery of drug-like O-GlcNAcase inhibitor scaffolds

Dorfmueller, Helge C.; van Aalten, Daan M.F.

doi:10.1016/j.febslet.2009.12.020

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Volume 584, Issue 4 , Pages 694-700, 19 February 2010

Screening-based discovery of drug-like O-GlcNAcase inhibitor scaffolds

Edited by Judit Ovádi

Division of Molecular Microbiology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK

Received 16 October 2009; received in revised form 1 December 2009; accepted 13 December 2009. published online 17 December 2009.

Abstract

O-GlcNAcylation is an essential posttranslational modification in metazoa. Modulation of O-GlcNAc levels with small molecule inhibitors of O-GlcNAc hydrolase (OGA) is a useful strategy to probe the role of this modification in a range of cellular processes. Here we report the discovery of novel, low molecular weight and drug-like O-GlcNAcase inhibitor scaffolds by high-throughput screening. Kinetic and X-ray crystallographic analyses of the binding modes with human/bacterial O-GlcNAcases identify some of these as competitive inhibitors. Comparative kinetic experiments with the mechanistically related human lysosomal hexosaminidases reveal that three of the inhibitor scaffolds show selectivity towards human OGA. These scaffolds provide attractive starting points for the development of non-carbohydrate, drug-like OGA inhibitors.

Keywords: O-GlcNAc, Posttranslational modification, Inhibitor, Crystal structure