4JJS

Crystal structure of HCV NS5B polymerase in complex with COMPOUND 2

4JJS の概要

• エントリーDOI: 10.2210/pdb4jjs/pdb
• 関連するPDBエントリー: 3MWV 4JJU
• 分子名称: Genome polyprotein, 2-{[(trans-4-methylcyclohexyl)carbonyl](propan-2-yl)amino}-5-[2-(trifluoromethyl)phenoxy]benzoic acid, MAGNESIUM ION, ... (4 entities in total)
• 機能のキーワード: laval, hcv virus rdrp ns5b polymerase, transferase, 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: 129083.37

構造登録者

Coulombe, R. (登録日: 2013-03-08, 公開日: 2013-06-12, 最終更新日: 2024-02-28)

主引用文献

Beaulieu, P.L.,Coulombe, R.,Duan, J.,Fazal, G.,Godbout, C.,Hucke, O.,Jakalian, A.,Joly, M.A.,Lepage, O.,Llinas-Brunet, M.,Naud, J.,Poirier, M.,Rioux, N.,Thavonekham, B.,Kukolj, G.,Stammers, T.A.
Structure-based design of novel HCV NS5B thumb pocket 2 allosteric inhibitors with submicromolar gt1 replicon potency: Discovery of a quinazolinone chemotype.
Bioorg.Med.Chem.Lett., 23:4132-4140, 2013

PubMed Abstract: We describe the structure-based design of a novel lead chemotype that binds to thumb pocket 2 of HCV NS5B polymerase and inhibits cell-based gt1 subgenomic reporter replicons at sub-micromolar concentrations (EC50<200nM). This new class of potent thumb pocket 2 inhibitors features a 1H-quinazolin-4-one scaffold derived from hybridization of a previously reported, low affinity thiazolone chemotype with our recently described anthranilic acid series. Guided by X-ray structural information, a key NS5B-ligand interaction involving the carboxylate group of anthranilic acid based inhibitors was replaced by a neutral two-point hydrogen bonding interaction between the quinazolinone scaffold and the protein backbone. The in vitro ADME and in vivo rat PK profile of representative analogs are also presented and provide areas for future optimization of this new class of HCV polymerase inhibitors.

PubMed: 23768906
DOI: 10.1016/j.bmcl.2013.05.037

実験手法

X-RAY DIFFRACTION (2.2 Å)