2NSD

Enoyl acyl carrier protein reductase InhA in complex with N-(4-methylbenzoyl)-4-benzylpiperidine

2NSD の概要

• エントリーDOI: 10.2210/pdb2nsd/pdb
• 関連するPDBエントリー: 1P45 2H7I 2H7L 2H7M 2H7N 2H7P
• 分子名称: Enoyl-[acyl-carrier-protein] reductase, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, N-(4-METHYLBENZOYL)-4-BENZYLPIPERIDINE, ... (4 entities in total)
• 機能のキーワード: oxidoreductase, inha, enoyl acyl carrier reductase, n-(4-methylbenzoyl)-4-benzylpiperidine
• 由来する生物種: Mycobacterium tuberculosis H37Rv
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 59023.22

構造登録者

He, X.,Alian, A.,Ortiz de Montellano, P.R. (登録日: 2006-11-03, 公開日: 2007-09-18, 最終更新日: 2023-08-30)

主引用文献

He, X.,Alian, A.,Ortiz de Montellano, P.R.
Inhibition of the Mycobacterium tuberculosis enoyl acyl carrier protein reductase InhA by arylamides.
Bioorg.Med.Chem., 15:6649-6658, 2007

PubMed Abstract: InhA, the enoyl acyl carrier protein reductase (ENR) from Mycobacterium tuberculosis, is one of the key enzymes involved in the type II fatty acid biosynthesis pathway of M. tuberculosis. We report here the discovery, through high-throughput screening, of a series of arylamides as a novel class of potent InhA inhibitors. These direct InhA inhibitors require no mycobacterial enzymatic activation and thus circumvent the resistance mechanism to antitubercular prodrugs such as INH and ETA that is most commonly observed in drug-resistant clinical isolates. The crystal structure of InhA complexed with one representative inhibitor reveals the binding mode of the inhibitor within the InhA active site. Further optimization through a microtiter synthesis strategy followed by in situ activity screening led to the discovery of a potent InhA inhibitor with in vitro IC(50)=90 nM, representing a 34-fold potency improvement over the lead compound.

PubMed: 17723305
DOI: 10.1016/j.bmc.2007.08.013

実験手法

X-RAY DIFFRACTION (1.9 Å)