Application of Fragment‐Based Drug Discovery against DNA Gyrase B. Issue 8 (24th June 2015)

• Record Type: Journal Article
• Authors: Chen, Guo‐Ying; Ng, Fui Mee; Tan, Yih Wan; Poulsen, Anders; Seetoh, Weiguang; Lin, Grace; Kang, CongBao; Then, Siew Wen; Ahmad, Nur Huda; Wong, Ying Lei; Ng, Hui Qi; Chia, C. S. Brian; Lau, Qiu Ying; Hill, Jeffrey; Hung, Alvin W.; Keller, Thomas H.
• Is Part Of: ChemPlusChem. Volume 80:Issue 8(2015:Aug.)
• Page Start: 1250
• Page End: 1254
• Publication Date: 2015-06-24
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1002/cplu.201500197
• Languages: English
• ISSNs: 2192-6506

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>Bacterial resistance to antibiotics remains a serious threat to global health. The gyrase B enzyme is a well‐validated target for developing antibacterial drugs. Despite being an attractive target for antibiotic development, there are currently no gyrase B inhibitory drugs on the market. A fragment screen using 1, 800 compounds identified 14 fragments that bind to <italic>Escherichia coli (E. coli</italic>) gyrase B. The detailed characterization of binding is described for all 14 fragments. With the aid of X‐ray crystallography, modifications on a low‐affinity fragment (<italic>K</italic>_D=253 μ<sc>M</sc>, IC₅₀=634 μ<sc>M</sc>) has led to the development of a new class of potent phenyl aminopyrazole inhibitors against <italic>E. coli</italic> gyrase B (IC₅₀=160 n<sc>M</sc>). 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.</p> </abstract>