2YOJ

HCV NS5B polymerase complexed with pyridonylindole compound

2YOJ の概要

• エントリーDOI: 10.2210/pdb2yoj/pdb
• 分子名称: RNA-DIRECTED RNA POLYMERASE, 4-fluoranyl-6-[(7-fluoranyl-4-oxidanylidene-3H-quinazolin-6-yl)methyl]-8-(2-oxidanylidene-1H-pyridin-3-yl)furo[2,3-e]indole-7-carboxylic acid, PHOSPHATE ION, ... (4 entities in total)
• 機能のキーワード: transferase, inhibitor
• 由来する生物種: HEPATITIS C VIRUS
• 細胞内の位置: Core protein p21: Host endoplasmic reticulum membrane ; Single-pass membrane protein . Core protein p19: Virion . Envelope glycoprotein E1: Virion membrane ; Single-pass type I membrane protein . Envelope glycoprotein E2: Virion membrane ; Single-pass type I membrane protein . p7: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . Protease NS2-3: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . Serine protease NS3: Host endoplasmic reticulum membrane ; Peripheral membrane protein . Non-structural protein 4A: Host endoplasmic reticulum membrane ; Single-pass type I membrane protein . Non-structural protein 4B: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . Non-structural protein 5A: Host endoplasmic reticulum membrane ; Peripheral membrane protein . RNA-directed RNA polymerase: Host endoplasmic reticulum membrane ; Single-pass type I membrane protein : O92972
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 131996.29

構造登録者

Chen, K.X.,Venkatraman, S.,Anilkumar, G.N.,Zeng, Q.,Lesburg, C.A.,Vibulbhan, B.,Yang, W.,Velazquez, F.,Chan, T.-Y.,Bennett, F.,Sannigrahi, M.,Jiang, Y.,Duca, J.S.,Pinto, P.,Gavalas, S.,Huang, Y.,Wu, W.,Selyutin, O.,Agrawal, S.,Feld, B.,Huang, H.-C.,Li, C.,Cheng, K.-C.,Shih, N.-Y.,Kozlowski, J.A.,Rosenblum, S.B.,Njoroge, F.G. (登録日: 2012-10-24, 公開日: 2013-10-09, 最終更新日: 2024-05-08)

主引用文献

Chen, K.X.,Venkatraman, S.,Anilkumar, G.N.,Zeng, Q.,Lesburg, C.A.,Vibulbhan, B.,Velazquez, F.,Chan, T.-Y.,Bennett, F.,Jiang, Y.,Pinto, P.,Huang, Y.,Selyutin, O.,Agrawal, S.,Huang, H.-C.,Li, C.,Cheng, K.-C.,Shih, N.-Y.,Kozlowski, J.A.,Rosenblum, S.B.,Njoroge, F.G.
Discovery of Sch 900188: A Potent Hepatitis C Virus Ns5B Polymerase Inhibitor Prodrug as a Development Candidate
Acs Med.Chem.Lett., 5:244-, 2014

PubMed Abstract: Starting from indole-based hepatitis C virus (HCV) NS5B polymerase inhibitor lead compound 1, structure modifications were performed at multiple indole substituents to improve potency and pharmacokinetic (PK) properties. Bicyclic quinazolinone was found to be the best substituent at indole nitrogen, while 4,5-furanylindole was identified as the best core. Compound 11 demonstrated excellent potency. Its C2 N,N-dimethylaminoethyl ester prodrug 12 (SCH 900188) demonstrated significant improvement in PK and was selected as the development candidate.

PubMed: 24900812
DOI: 10.1021/ML400192W

実験手法

X-RAY DIFFRACTION (1.76 Å)