2FVC

Crystal structure of NS5B BK strain (delta 24) in complex with a 3-(1,1-Dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinone

2FVC の概要

• エントリーDOI: 10.2210/pdb2fvc/pdb
• 分子名称: polyprotein, 3-(1,1-dioxido-4H-1,2,4-benzothiadiazin-3-yl)-4-hydroxy-1-(3-methylbutyl)quinolin-2(1H)-one (3 entities in total)
• 機能のキーワード: hcv polymerase, thiadiazin inhibitor, transferase
• 由来する生物種: Hepatitis C virus subtype 1b
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 125688.11

構造登録者

Concha, N.O.,Wonacott, A.,Singh, O. (登録日: 2006-01-30, 公開日: 2007-01-16, 最終更新日: 2023-08-30)

主引用文献

Tedesco, R.,Shaw, A.N.,Bambal, R.,Chai, D.,Concha, N.O.,Darcy, M.G.,Dhanak, D.,Fitch, D.M.,Gates, A.,Gerhardt, W.G.,Halegoua, D.L.,Han, C.,Hofmann, G.A.,Johnston, V.K.,Kaura, A.C.,Liu, N.,Keenan, R.M.,Lin-Goerke, J.,Sarisky, R.T.,Wiggall, K.J.,Zimmerman, M.N.,Duffy, K.J.
3-(1,1-dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones, potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase.
J.Med.Chem., 49:971-983, 2006

PubMed Abstract: Recently, we disclosed a new class of HCV polymerase inhibitors discovered through high-throughput screening (HTS) of the GlaxoSmithKline proprietary compound collection. This interesting class of 3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones potently inhibits HCV polymerase enzymatic activity and inhibits the ability of the subgenomic HCV replicon to replicate in Huh-7 cells. This report will focus on the structure-activity relationships (SAR) of substituents on the quinolinone ring, culminating in the discovery of 1-(2-cyclopropylethyl)-3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-6-fluoro-4-hydroxy-2(1H)-quinolinone (130), an inhibitor with excellent potency in biochemical and cellular assays possessing attractive molecular properties for advancement as a clinical candidate. The potential for development and safety assessment profile of compound 130 will also be discussed.

PubMed: 16451063
DOI: 10.1021/jm050855s

実験手法

X-RAY DIFFRACTION (2 Å)