2. Academic Validation
  3. Fragment-Based Design of Mycobacterium tuberculosis InhA Inhibitors

Fragment-Based Design of Mycobacterium tuberculosis InhA Inhibitors

  • J Med Chem. 2020 May 14;63(9):4749-4761. doi: 10.1021/acs.jmedchem.0c00007.
Mohamad Sabbah 1,  Vitor Mendes 2,  Robert G Vistal 1,  David M G Dias 1,  Monika Záhorszká 3,  Katarína Mikušová 3,  Jana Korduláková 3,  Anthony G Coyne 1,  Tom L Blundell 2,  Chris Abell 1
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
  • 2 Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, United Kingdom.
  • 3 Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Mlynská dolina, Ilkovičova 6, 84215 Bratislava, Slovakia.
PMID: 32240584 DOI: 10.1021/acs.jmedchem.0c00007
Abstract

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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