5G0U: Inha In Complex With A Dna Encoded Library Hit

Citation:
Abstract
Millions of individuals are infected with and die from tuberculosis (TB) each year, and multidrug-resistant (MDR) strains of TB are increasingly prevalent. As such, there is an urgent need to identify novel drugs to treat TB infections. Current frontline therapies include the drug isoniazid, which inhibits the essential NADH-dependent enoyl-acyl-carrier protein (ACP) reductase, InhA. To inhibit InhA, isoniazid must be activated by the catalase-peroxidase KatG. Isoniazid resistance is linked primarily to mutations in the katG gene. Discovery of InhA inhibitors that do not require KatG activation is crucial to combat MDR TB. Multiple discovery efforts have been made against InhA in recent years. Until recently, despite achieving high potency against the enzyme, these efforts have been thwarted by lack of cellular activity. We describe here the use of DNA-encoded X-Chem (DEX) screening, combined with selection of appropriate physical properties, to identify multiple classes of InhA inhibitors with cell-based activity. The utilization of DEX screening allowed the interrogation of very large compound libraries (1011 unique small molecules) against multiple forms of the InhA enzyme in a multiplexed format. Comparison of the enriched library members across various screening conditions allowed the identification of cofactor-specific inhibitors of InhA that do not require activation by KatG, many of which had bactericidal activity in cell-based assays.
PDB ID: 5G0UDownload
MMDB ID: 145229
PDB Deposition Date: 2016/3/22
Updated in MMDB: 2016/12
Experimental Method:
x-ray diffraction
Resolution: 1.73  Å
Source Organism:
Similar Structures:
Biological Unit for 5G0U: tetrameric; determined by author and by software (PISA)
Molecular Components in 5G0U
Label Count Molecule
Proteins (4 molecules)
4
Enoyl-[acyl-carrier-protein] Reductase [nadh](Gene symbol: inhA)
Molecule annotation
Chemicals (6 molecules)
1
4
2
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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