2FOI

Synthesis, Biological Activity, and X-Ray Crystal Structural Analysis of Diaryl Ether Inhibitors of Malarial Enoyl ACP Reductase.

2FOI の概要

• エントリーDOI: 10.2210/pdb2foi/pdb
• 関連するPDBエントリー: 1NHD 1NHG 1NHW 1NNU 1ZSN 1ZW1
• 分子名称: enoyl-acyl carrier reductase, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, 4-(2,4-DICHLOROPHENOXY)-2'-METHYLBIPHENYL-3-OL, ... (5 entities in total)
• 機能のキーワード: enoyl reductase, rossmann fold, oxidoreductase
• 由来する生物種: Plasmodium falciparum; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 76405.39

構造登録者

Freundlich, J.S.,Shieh, H.,Anderson, J.W.,Kuo, M.,Yu, M.,Valderramos, J.,Karagyozov, L.,Tsai, H.,Lucumi, E.,Jacobs Jr., W.R.,Schiehser, G.A.,Jacobus, D.P.,Fidock, D.A.,Sacchettini, J.C. (登録日: 2006-01-13, 公開日: 2007-01-16, 最終更新日: 2023-08-30)

主引用文献

Freundlich, J.S.,Wang, F.,Tsai, H.C.,Kuo, M.,Shieh, H.M.,Anderson, J.W.,Nkrumah, L.J.,Valderramos, J.C.,Yu, M.,Kumar, T.R.,Valderramos, S.G.,Jacobs, W.R.,Schiehser, G.A.,Jacobus, D.P.,Fidock, D.A.,Sacchettini, J.C.
X-ray Structural Analysis of Plasmodium falciparum Enoyl Acyl Carrier Protein Reductase as a Pathway toward the Optimization of Triclosan Antimalarial Efficacy.
J.Biol.Chem., 282:25436-25444, 2007

PubMed Abstract: The x-ray crystal structures of five triclosan analogs, in addition to that of the isoniazid-NAD adduct, are described in relation to their integral role in the design of potent inhibitors of the malarial enzyme Plasmodium falciparum enoyl acyl carrier protein reductase (PfENR). Many of the novel 5-substituted analogs exhibit low micromolar potency against in vitro cultures of drug-resistant and drug-sensitive strains of the P. falciparum parasite and inhibit purified PfENR enzyme with IC50 values of <200 nM. This study has significantly expanded the knowledge base with regard to the structure-activity relationship of triclosan while affording gains against cultured parasites and purified PfENR enzyme. In contrast to a recent report in the literature, these results demonstrate the ability to improve the in vitro potency of triclosan significantly by replacing the suboptimal 5-chloro group with larger hydrophobic moieties. The biological and x-ray crystallographic data thus demonstrate the flexibility of the active site and point to future rounds of optimization to improve compound potency against purified enzyme and intracellular Plasmodium parasites.

PubMed: 17567585
DOI: 10.1074/jbc.M701813200

実験手法

X-RAY DIFFRACTION (2.5 Å)