4.7 Article

Fragment-Based Design of Mycobacterium tuberculosis InhA Inhibitors

期刊

JOURNAL OF MEDICINAL CHEMISTRY
卷 63, 期 9, 页码 4749-4761

出版社

AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c00007

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资金

  1. Bill and Melinda Gates Foundation
  2. Foundation for the National Institute of Health (NIH) [OPP1024021]
  3. Foundation for the National Institutes of Health (FNIH) [OPP1158806]
  4. European Community [260872]
  5. FCT PhD grant [SFRH/BD/81735/2011]
  6. Ministry of Education, Science, Research and Sport of the Slovak Republic [VEGA 1/0301/18]
  7. Slovak Research and Development Agency [DO7RP-0015-11]
  8. Research and Development Operational Programme - European Regional Development Fund [ITMS 26240120027]
  9. Fundação para a Ciência e a Tecnologia [SFRH/BD/81735/2011] Funding Source: FCT

向作者/读者索取更多资源

Tuberculosis (TB) remains a leading cause of mortality among infectious diseases worldwide. InhA has been the focus of numerous drug discovery efforts as this is the target of the first line pro-drug isoniazid. However, with resistance to this drug becoming more common, the aim has been to find new clinical candidates that directly inhibit this enzyme and that do not require activation by the catalase peroxidase KatG, thus circumventing the majority of the resistance mechanisms. In this work, the screening and validation of a fragment library are described, and the development of the fragment hits using a fragment growing strategy was employed, which led to the development of InhA inhibitors with affinities of up to 250 nM.

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