Premium
Screening‐based discovery of drug‐like O ‐GlcNAcase inhibitor scaffolds
Author(s) -
Dorfmueller Helge C.,
van Aalten Daan M.F.
Publication year - 2010
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2009.12.020
Subject(s) - drug discovery , chemistry , small molecule , enzyme , hydrolase , drug , selectivity , high throughput screening , biochemistry , biology , pharmacology , catalysis
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.