Application of Fragment-Based Drug Discovery against DNA GyraseB

被引：14

作者：

Chen, Guo-Ying ^{[1
]}

Ng, Fui Mee ^{[1
]}

Tan, Yih Wan ^{[1
]}

Poulsen, Anders ^{[1
]}

Seetoh, Weiguang ^{[1
]}

Lin, Grace ^{[1
]}

Kang, CongBao ^{[1
]}

Then, Siew Wen ^{[1
]}

Ahmad, Nur Huda ^{[1
]}

Wong, Ying Lei ^{[1
]}

Ng, Hui Qi ^{[1
]}

Chia, C. S. Brian ^{[1
]}

Lau, Qiu Ying ^{[1
]}

Hill, Jeffrey ^{[1
]}

Hung, Alvin W. ^{[1
]}

Keller, Thomas H. ^{[1
]}

机构：

[1] ASTAR, Ctr Expt Therapeut, Singapore 138667, Singapore

来源：

CHEMPLUSCHEM | 2015年 / 80卷 / 08期

关键词：

antibiotics; drug design; drug discovery; inhibitors; ligand effects; MYCOBACTERIUM-TUBERCULOSIS; ANTIBACTERIAL AGENTS; TOPOISOMERASE-IV; B PROTEIN; INHIBITORS; OPTIMIZATION; POTENT; HIT; RESISTANCE; DESIGN;

D O I：

10.1002/cplu.201500197

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Bacterial resistance to antibiotics remains a serious threat to global health. The gyraseB enzyme is a well-validated target for developing antibacterial drugs. Despite being an attractive target for antibiotic development, there are currently no gyraseB inhibitory drugs on the market. A fragment screen using 1,800compounds identified 14fragments that bind to Escherichia coli (E.coli) gyraseB. The detailed characterization of binding is described for all 14fragments. With the aid of X-ray crystallography, modifications on a low-affinity fragment (K-D=253M, IC50=634M) has led to the development of a new class of potent phenyl aminopyrazole inhibitors against E.coli gyraseB (IC50=160nM). The study presented here combines the use of a set of biophysical techniques including differential scanning fluorimetry, nuclear magnetic resonance, isothermal titration calorimetry, and X-ray crystallography to methodically identify, quantify, and optimize fragments into new chemical leads.

引用

页码：1250 / 1254

页数：5

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