5G0S

InhA in complex with a DNA encoded library hit

Summary for 5G0S

• Entry DOI: 10.2210/pdb5g0s/pdb
• Related: 5G0T 5G0U 5G0V 5G0W
• Descriptor: ENOYL-[ACYL-CARRIER-PROTEIN] REDUCTASE [NADH], NICOTINAMIDE-ADENINE-DINUCLEOTIDE, N-[4-[2-[(2S)-4-[2-(methylamino)-2-oxidanylidene-ethyl]-3-oxidanylidene-2-(phenylmethyl)piperazin-1-yl]-2-oxidanylidene-ethyl]cyclohexyl]-2-(3-methyl-1-benzothiophen-2-yl)ethanamide, ... (4 entities in total)
• Functional Keywords: oxidoreductase, inha, acp enoyl reductase, dna encoded library, del, tuberculosis
• Biological source: MYCOBACTERIUM TUBERCULOSIS
• Total number of polymer chains: 4
• Total formula weight: 118050.34

Authors

Read, J.A.,Breed, J. (deposition date: 2016-03-22, release date: 2016-11-30, Last modification date: 2024-01-10)

Primary citation

Soutter, H.H.,Centrella, P.,Clark, M.A.,Cuozzo, J.W.,Dumelin, C.E.,Guie, M.-A.,Habeshian, S.,Keefe, A.D.,Kennedy, K.M.,Sigel, E.A.,Troast, D.M.,Zhang, Y.,Ferguson, A.D.,Davies, G.,Stead, E.R.,Breed, J.,Madhavapeddi, P.,Read, J.A.
Discovery of Cofactor-Specific, Bactericidal Mycobacterium Tuberculosis Inha Inhibitors Using DNA-Encoded Library Technology
Proc.Natl.Acad.Sci.USA, 113:E7780-, 2016

PubMed 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 (10 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.

PubMed: 27864515
DOI: 10.1073/PNAS.1610978113

Experimental method

X-RAY DIFFRACTION (1.74 Å)