PDBsum entry 2fvc

Transferase

PDB id: 2fvc

Contents

Protein chains

563 a.a. *

Ligands

888 ×2

Waters ×641

* Residue conservation analysis

PDB id:

2fvc

Name:

Transferase

Title:

Crystal structure of ns5b bk strain (delta 24) in complex with a 3-(1, 1-dioxo-2h-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1h)-quinolinone

Structure:

Polyprotein. Chain: a, b. Engineered: yes

Source:

Hepatitis c virus subtype 1b. Organism_taxid: 31647. Strain: bk. Gene: ns5b. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

2.00Å R-factor: 0.206 R-free: 0.243

Authors:

N.O.Concha,A.Wonacott,O.Singh

Key ref:

R.Tedesco et al. (2006). 3-(1,1-dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones, potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase. J Med Chem, 49, 971-983. PubMed id: 16451063 DOI: 10.1021/jm050855s

Date:

30-Jan-06 Release date: 16-Jan-07

Protein chains

Q99AU2  (Q99AU2_9HEPC) -  Genome polyprotein from Hepatitis C virus subtype 1b

Seq: 3010 a.a.

Struc: 563 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class 1: E.C.3.4.21.98 - hepacivirin.
• Reaction: Hydrolysis of four peptide bonds in the viral precursor polyprotein, commonly with Asp or Glu in the P6 position, Cys or Thr in P1 and Ser or Ala in P1'.
• Enzyme class 2: E.C.3.6.1.15 - nucleoside-triphosphate phosphatase.
• Reaction: a ribonucleoside 5'-triphosphate + H2O = a ribonucleoside 5'-diphosphate + phosphate + H⁺
• Enzyme class 3: E.C.3.6.4.13 - Rna helicase.
• Reaction: ATP + H2O = ADP + phosphate + H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/jm050855s

J Med Chem 49:971-983 (2006)

PubMed id: 16451063

3-(1,1-dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones, potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase.

R.Tedesco, A.N.Shaw, R.Bambal, D.Chai, N.O.Concha, M.G.Darcy, D.Dhanak, D.M.Fitch, A.Gates, W.G.Gerhardt, D.L.Halegoua, C.Han, G.A.Hofmann, V.K.Johnston, A.C.Kaura, N.Liu, R.M.Keenan, J.Lin-Goerke, R.T.Sarisky, K.J.Wiggall, M.N.Zimmerman, K.J.Duffy.

ABSTRACT

Recently, we disclosed a new class of HCV polymerase inhibitors discovered through high-throughput screening (HTS) of the GlaxoSmithKline proprietary compound collection. This interesting class of 3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones potently inhibits HCV polymerase enzymatic activity and inhibits the ability of the subgenomic HCV replicon to replicate in Huh-7 cells. This report will focus on the structure-activity relationships (SAR) of substituents on the quinolinone ring, culminating in the discovery of 1-(2-cyclopropylethyl)-3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-6-fluoro-4-hydroxy-2(1H)-quinolinone (130), an inhibitor with excellent potency in biochemical and cellular assays possessing attractive molecular properties for advancement as a clinical candidate. The potential for development and safety assessment profile of compound 130 will also be discussed.