3SKE

I. Novel HCV NS5B Polymerase Inhibitors: Discovery of Indole 2- Carboxylic Acids with C3-Heterocycles

3SKE の概要

• エントリーDOI: 10.2210/pdb3ske/pdb
• 関連するPDBエントリー: 3SKA 3SKH
• 分子名称: HCV NS5B RNA_DEPENDENT RNA POLYMERASE, PHOSPHATE ION, 1-[(2-aminopyridin-4-yl)methyl]-3-(2,4-dioxo-1,2-dihydrothieno[3,4-d]pyrimidin-3(4H)-yl)-5-(trifluoromethyl)-1H-indole-2-carboxylic acid, ... (4 entities in total)
• 機能のキーワード: rna-dependent rna polymerase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Hepatitis C virus isolate HC-J4 (HCV)
• 細胞内の位置: Core protein p21: Host endoplasmic reticulum membrane; Single-pass membrane protein (By similarity). Core protein p19: Virion (By similarity). Envelope glycoprotein E1: Virion membrane; Single-pass type I membrane protein (Potential). Envelope glycoprotein E2: Virion membrane; Single-pass type I membrane protein (Potential). p7: Host endoplasmic reticulum membrane; Multi-pass membrane protein (By similarity). Protease NS2-3: Host endoplasmic reticulum membrane; Multi-pass membrane protein (Potential). Serine protease NS3: Host endoplasmic reticulum membrane; Peripheral membrane protein (By similarity). Non-structural protein 4A: Host endoplasmic reticulum membrane; Single-pass type I membrane protein (Potential). Non-structural protein 4B: Host endoplasmic reticulum membrane; Multi-pass membrane protein (By similarity). Non-structural protein 5A: Host endoplasmic reticulum membrane; Peripheral membrane protein (By similarity). RNA-directed RNA polymerase: Host endoplasmic reticulum membrane; Single-pass type I membrane protein (Potential): O92972
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 129481.01

構造登録者

Lesburg, C.A.,Anilkumar, G.N. (登録日: 2011-06-22, 公開日: 2011-08-31, 最終更新日: 2024-11-27)

主引用文献

Anilkumar, G.N.,Lesburg, C.A.,Selyutin, O.,Rosenblum, S.B.,Zeng, Q.,Jiang, Y.,Chan, T.Y.,Pu, H.,Vaccaro, H.,Wang, L.,Bennett, F.,Chen, K.X.,Duca, J.,Gavalas, S.,Huang, Y.,Pinto, P.,Sannigrahi, M.,Velazquez, F.,Venkatraman, S.,Vibulbhan, B.,Agrawal, S.,Butkiewicz, N.,Feld, B.,Ferrari, E.,He, Z.,Jiang, C.K.,Palermo, R.E.,McMonagle, P.,Huang, H.C.,Shih, N.Y.,Njoroge, G.,Kozlowski, J.A.
I. Novel HCV NS5B polymerase inhibitors: discovery of indole 2-carboxylic acids with C3-heterocycles.
Bioorg.Med.Chem.Lett., 21:5336-5341, 2011

PubMed Abstract: SAR development of indole-based palm site inhibitors of HCV NS5B polymerase exemplified by initial indole lead 1 (NS5B IC(50)=0.9 μM, replicon EC(50)>100 μM) is described. Structure-based drug design led to the incorporation of novel heterocyclic moieties at the indole C3-position which formed a bidentate interaction with the protein backbone. SAR development resulted in leads 7q (NS5B IC(50)=0.032 μM, replicon EC(50)=1.4 μM) and 7r (NS5B IC(50)=0.017 μM, replicon EC(50)=0.3 μM) with improved enzyme and replicon activity.

PubMed: 21840715
DOI: 10.1016/j.bmcl.2011.07.021

実験手法

X-RAY DIFFRACTION (1.97 Å)