4U0J

Crystal structure of Mycobacterium tuberculosis enoyl reductase (INHA) complexed with 1-CYCLOHEXYL-5-OXO-N-PHENYLPYRROLIDINE-3-CARBOXAMIDE, refined with new ligand restraints

「2H7I」から置き換えられました

4U0J の概要

• エントリーDOI: 10.2210/pdb4u0j/pdb
• 関連するPDBエントリー: 4TRJ 4TZK 4TZT 4U0K
• 分子名称: Enoyl-[acyl-carrier-protein] reductase [NADH], NICOTINAMIDE-ADENINE-DINUCLEOTIDE, (3S)-1-CYCLOHEXYL-5-OXO-N-PHENYLPYRROLIDINE-3-CARBOXAMIDE, ... (4 entities in total)
• 機能のキーワード: oxidoreductase, pyrrolidine carboxamide
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29504.57

構造登録者

He, X.,Alian, A.,Stroud, R.M.,Ortiz de Montellano, P.R. (登録日: 2014-07-11, 公開日: 2014-07-30, 最終更新日: 2023-12-27)

主引用文献

He, X.,Alian, A.,Stroud, R.M.,Ortiz de Montellano, P.R.
Pyrrolidine carboxamides as a novel class of inhibitors of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis
J. Med. Chem., :6308-6323, 2006

PubMed Abstract: In view of the worldwide spread of multidrug resistance of Mycobacterium tuberculosis, there is an urgent need to discover antituberculosis agent with novel structures. InhA, the enoyl acyl carrier protein reductase (ENR) from M. tuberculosis, is one of the key enzymes involved in the mycobacterial fatty acid elongation cycle and has been validated as an effective antimicrobial target. We report here the discovery, through high-throughput screening, of a series of pyrrolidine carboxamides as a novel class of potent InhA inhibitors. Crystal structures of InhA complexed with three inhibitors have been used to elucidate the inhibitor binding mode. The potency of the lead compound was improved over 160-fold by subsequent optimization through iterative microtiter library synthesis followed by in situ activity screening without purification. Resolution of racemic mixtures of several inhibitors indicate that only one enantiomer is active as an inhibitor of InhA.

PubMed: 17034137
DOI: 10.1021/JM060715Y

実験手法

X-RAY DIFFRACTION (1.62 Å)