2X0Y

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

Summary for 2X0Y

• Entry DOI: 10.2210/pdb2x0y/pdb
• Related: 2CBI 2CBJ 2J62 2JH2 2V5C 2V5D 2VUR 2WB5
• Descriptor: O-GLCNACASE NAGJ, 7-[(2S)-2,3-DIHYDROXYPROPYL]-1,3-DIMETHYL-3,7-DIHYDRO-1H-PURINE-2,6-DIONE (3 entities in total)
• Functional Keywords: glycosidase, hydrolase, cell adhesion
• Biological source: CLOSTRIDIUM PERFRINGENS
• Total number of polymer chains: 2
• Total formula weight: 133885.91

Authors

Dorfmueller, H.C.,van Aalten, D.M.F. (deposition date: 2009-12-18, release date: 2010-01-12, Last modification date: 2023-12-20)

Primary citation

Dorfmueller, H.C.,Van Aalten, D.M.F.
Screening-Based Discovery of Drug-Like O-Glcnacase Inhibitor Scaffolds
FEBS Lett., 584:694-, 2010

PubMed 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.

PubMed: 20026047
DOI: 10.1016/J.FEBSLET.2009.12.020

Experimental method

X-RAY DIFFRACTION (2.25 Å)