5G0V

InhA in complex with a DNA encoded library hit

5G0V の概要

• エントリーDOI: 10.2210/pdb5g0v/pdb
• 関連するPDBエントリー: 5G0S 5G0T 5G0U 5G0W
• 分子名称: ENOYL-ACYL CARRIER PROTEIN REDUCTASE, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: oxidoreductase, inha, acp enoyl reductase, dna encoded library, del, tuberculosis
• 由来する生物種: MYCOBACTERIUM TUBERCULOSIS
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 117329.65

構造登録者

Read, J.A.,Breed, J. (登録日: 2016-03-22, 公開日: 2016-11-30, 最終更新日: 2024-01-10)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.79 Å)