期刊
CHEMICAL BIOLOGY & DRUG DESIGN
卷 84, 期 6, 页码 685-696出版社
WILEY-BLACKWELL
DOI: 10.1111/cbdd.12361
关键词
antibacterial activity; glycosyltransferase; isatin derivatives; STD-NMR; virtual screening
资金
- Hong Kong Polytechnic University
- Research Grants Council [PolyU 5026/09P]
- Special Equipment Grant from the University Grants Committee [SEG_PolyU01]
- Innovation and Technology Commission
Peptidoglycan glycosyltransferase (PGT) has been shown to be an important pharmacological target for the inhibition of bacterial cell wall biosynthesis. Structure-based virtual screening of about 3000000 commercially available compounds against the crystal structure of the glycosyltransferase (GT) domain of the Staphylococcus aureus penicillin-binding protein 2 (S.aureus PBP2) resulted in identification of an isatin derivative, 2-(3-(2-carbamimidoylhydrazono)-2-oxoindolin-1-yl)-N-(m-tolyl)acetamide (4) as a novel potential GT inhibitor. A series of 4 derivatives were synthesized. Several compounds showed more active antimicrobial activity than the initial hit compound 4, in particular 2-(3-(2-carbamimidoylhydrazono)-2-oxoindolin-1-yl)-N-(3-nitrophenyl)acetamide (4l), against Gram-positive Bacillus subtilis and S.aureus with MIC values of 24 and 48g/mL, respectively. Saturation transfer difference (STD) NMR study revealed that there is a binding contact between 4l and the GT domain of S.aureus PBP2. Competitive STD-NMR further proved that 4l and moenomycin A bind to GT domain in a competitive manner. Molecular docking study suggests a potential binding pocket of 4l in the GT domain of S.aureus PBP2. Taken together, compound 4l would provide a new scaffold for further development of potent GT inhibitors.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据