4MK9

Hepatitis C Virus polymerase NS5B genotype 1b (BK) in complex with inhibitor 12 (N-{2-[3-tert-butyl-2-methoxy-5-(2-oxo-1,2-dihydropyridin-3-yl)phenyl]-1,3-benzoxazol-5-yl}methanesulfonamide)

4MK9 の概要

• エントリーDOI: 10.2210/pdb4mk9/pdb
• 関連するPDBエントリー: 4MIA 4MIB 4MK7 4MK8 4MKA 4MKB
• 分子名称: RNA-DIRECTED RNA POLYMERASE, N-{2-[3-tert-butyl-2-methoxy-5-(2-oxo-1,2-dihydropyridin-3-yl)phenyl]-1,3-benzoxazol-5-yl}methanesulfonamide, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: polymerase, transferase, ns5b, 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 (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): P26663
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 127736.61

構造登録者

Harris, S.F.,Wong, A. (登録日: 2013-09-04, 公開日: 2013-10-09, 最終更新日: 2024-02-28)

主引用文献

Schoenfeld, R.C.,Bourdet, D.L.,Brameld, K.A.,Chin, E.,de Vicente, J.,Fung, A.,Harris, S.F.,Lee, E.K.,Le Pogam, S.,Leveque, V.,Li, J.,Lui, A.S.,Najera, I.,Rajyaguru, S.,Sangi, M.,Steiner, S.,Talamas, F.X.,Taygerly, J.P.,Zhao, J.
Discovery of a Novel Series of Potent Non-Nucleoside Inhibitors of Hepatitis C Virus NS5B.
J.Med.Chem., 56:8163-8182, 2013

PubMed Abstract: Hepatitis C virus (HCV) is a major global public health problem. While the current standard of care, a direct-acting antiviral (DAA) protease inhibitor taken in combination with pegylated interferon and ribavirin, represents a major advancement in recent years, an unmet medical need still exists for treatment modalities that improve upon both efficacy and tolerability. Toward those ends, much effort has continued to focus on the discovery of new DAAs, with the ultimate goal to provide interferon-free combinations. The RNA-dependent RNA polymerase enzyme NS5B represents one such DAA therapeutic target for inhibition that has attracted much interest over the past decade. Herein, we report the discovery and optimization of a novel series of inhibitors of HCV NS5B, through the use of structure-based design applied to a fragment-derived starting point. Issues of potency, pharmacokinetics, and early safety were addressed in order to provide a clinical candidate in fluoropyridone 19.

PubMed: 24069953
DOI: 10.1021/jm401266k

実験手法

X-RAY DIFFRACTION (2.05 Å)