3TYV

SAR development and discovery of potent indole-based inhibitors of the hepatitis C virus NS5B polymerase

3TYV の概要

• エントリーDOI: 10.2210/pdb3tyv/pdb
• 関連するPDBエントリー: 3TYQ
• 分子名称: RNA-directed RNA polymerase, PHOSPHATE ION, N-(cyclopropylsulfonyl)-1-(2,5-difluorobenzyl)-6-fluoro-5-methyl-3-(2-oxo-1,2-dihydropyridin-3-yl)-1H-indole-2-carboxamide, ... (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 (HCV)
• 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: 129509.14

構造登録者

Lesburg, C.A.,Chen, K.X. (登録日: 2011-09-26, 公開日: 2012-02-01, 最終更新日: 2024-10-16)

主引用文献

Chen, K.X.,Vibulbhan, B.,Yang, W.,Sannigrahi, M.,Velazquez, F.,Chan, T.Y.,Venkatraman, S.,Anilkumar, G.N.,Zeng, Q.,Bennet, F.,Jiang, Y.,Lesburg, C.A.,Duca, J.,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.
Structure-Activity Relationship (SAR) Development and Discovery of Potent Indole-Based Inhibitors of the Hepatitis C Virus (HCV) NS5B Polymerase.
J.Med.Chem., 55:754-765, 2012

PubMed Abstract: Starting with the indole-based C-3 pyridone lead HCV polymerase inhibitor 2, extensive SAR studies were performed at different positions of the indole core. The best C-5 groups were found to be compact and nonpolar moieties and that the C-6 attachments were not affecting potency. Limited N-1 benzyl-type substituent studies indicated that the best substitutions were fluoro or methyl groups at 2' or 5' positions of the benzyl group. To improve pharmacokinetic (PK) properties, acylsulfonamides were incorporated as acid isosteres at the C-2 position. Further optimization of the combination at N-1, C-2, C-5, and C-6 resulted in the identification of compound 56, which had an excellent potency in both NS5B enzyme (IC(50) = 0.008 μM) and cell-based replicon (EC(50) = 0.02 μM) assays and a good oral PK profile with area-under-the curve (AUC) of 14 and 8 μM·h in rats and dogs, respectively. X-ray structure of inhibitor 56 bound to the enzyme was also reported.

PubMed: 22148957
DOI: 10.1021/jm201258k

実験手法

X-RAY DIFFRACTION (1.65 Å)