کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2048190 1074069 2010 7 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Screening-based discovery of drug-like O-GlcNAcase inhibitor scaffolds
موضوعات مرتبط
علوم زیستی و بیوفناوری علوم کشاورزی و بیولوژیک دانش گیاه شناسی
پیش نمایش صفحه اول مقاله
Screening-based discovery of drug-like O-GlcNAcase inhibitor scaffolds
چکیده انگلیسی

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.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: FEBS Letters - Volume 584, Issue 4, 19 February 2010, Pages 694–700
نویسندگان
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