Fragment-Based Design of Mycobacterium tuberculosis InhA Inhibitors.
Accepted version
Peer-reviewed
Repository URI
Repository DOI
Change log
Authors
Sabbah, Mohamad
Mendes, Vitor https://orcid.org/0000-0002-2734-2444
Vistal, Robert G
Dias, David MG
Záhorszká, Monika
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.
Description
Keywords
Antitubercular Agents, Bacterial Proteins, Binding Sites, Drug Design, Enzyme Assays, Enzyme Inhibitors, Molecular Docking Simulation, Molecular Structure, Mycobacterium tuberculosis, Oxidoreductases, Protein Binding, Small Molecule Libraries, Structure-Activity Relationship, Sulfonamides
Journal Title
J Med Chem
Conference Name
Journal ISSN
0022-2623
1520-4804
1520-4804
Volume Title
63
Publisher
American Chemical Society (ACS)
Publisher DOI
Rights
All rights reserved
Sponsorship
European Commission (260872)