Application of Fragment-Based Drug Discovery against DNA Gyrase B

Application of Fragment-Based Drug Discovery against DNA Gyrase B
Title:
Application of Fragment-Based Drug Discovery against DNA Gyrase B
Other Titles:
ChemPlusChem
Publication Date:
24 June 2015
Citation:
Chen, G.-Y., Ng, F. M., Tan, Y. W., Poulsen, A., Seetoh, W., Lin, G., Kang, C., Then, S. W., Ahmad, N. H., Wong, Y. L., Ng, H. Q., Chia, C. S. B., Lau, Q. Y., Hill, J., Hung, A. W. and Keller, T. H. (2015), Application of Fragment-Based Drug Discovery against DNA Gyrase B. ChemPlusChem. doi: 10.1002/cplu.201500197
Abstract:
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 Escherichia coli (E. coli) 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 (KD=253 mm, IC50=634 mm) has led to the development of a new class of potent phenyl aminopyrazole inhibitors against E. coli gyrase B (IC50=160 nm). 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.
License type:
PublisherCopyrights
Funding Info:
A*STAR
Description:
This is the peer reviewed version of the following article: [Chen, G.-Y., Ng, F. M., Tan, Y. W., Poulsen, A., Seetoh, W., Lin, G., Kang, C., Then, S. W., Ahmad, N. H., Wong, Y. L., Ng, H. Q., Chia, C. S. B., Lau, Q. Y., Hill, J., Hung, A. W. and Keller, T. H. (2015), Application of Fragment-Based Drug Discovery against DNA Gyrase B. ChemPlusChem. doi: 10.1002/cplu.201500197], which has been published in final form at [https://doi.org/10.1002/cplu.201500197]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving
ISSN:
2192-6506
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