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Fragment-Based Design of Mycobacterium tuberculosis InhA Inhibitors.

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.

SUBMITTER: Sabbah M

PROVIDER: S-EPMC7232676 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Fragment-Based Design of <i>Mycobacterium tuberculosis</i> InhA Inhibitors.

Sabbah Mohamad M Mendes Vitor V Vistal Robert G RG Dias David M G DMG Záhorszká Monika M Mikušová Katarína K Korduláková Jana J Coyne Anthony G AG Blundell Tom L TL Abell Chris C

Journal of medicinal chemistry 20200415 9

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, th ...[more]

PMID: 32240584

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A virtual screen discovers novel, fragment-sized inhibitors of Mycobacterium tuberculosis InhA.

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2015-01-01 | GSE17424 | GEO

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