PDBsum entry 4jjs

Transferase/transferase inhibitor

PDB id: 4jjs

Contents

Protein chains

559 a.a.

Ligands

1M9

Metals

_MG ×2

Waters ×263

PDB id:

4jjs

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of hcv ns5b polymerase in complex with compound 2

Structure:

Genome polyprotein. Chain: a, b. Fragment: RNA-directed RNA polymerase, unp residues 2420-2989. Synonym: core protein p21, capsid protein c, p21, core protein p19, envelope glycoprotein e1, gp32, gp35, envelope glycoprotein e2, ns1, gp68, gp70, p7, protease ns2-3, p23, serine protease ns3, hepacivirin, ns3p, p70, non-structural protein 4a, ns4a, p8, non- structural protein 4b, ns4b, p27, non-structural protein 5a, ns5a, p56, RNA-directed RNA polymerase, ns5b, p68.

Source:

Hepatitis c virus. Hcv. Organism_taxid: 420174. Strain: ibj4. Gene: ns5b. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.20Å R-factor: 0.236 R-free: 0.272

Authors:

R.Coulombe

Key ref:

P.L.Beaulieu et al. (2013). 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. PubMed id: 23768906 DOI: 10.1016/j.bmcl.2013.05.037

Date:

08-Mar-13 Release date: 12-Jun-13

Protein chains

O92972  (POLG_HCVJ4) -  Genome polyprotein from Hepatitis C virus genotype 1b (strain HC-J4)

Seq: 3010 a.a.

Struc: 559 a.a.

Enzyme reactions

• Enzyme class 1: E.C.2.7.7.48 - RNA-directed Rna polymerase.
• Reaction: RNA(n) + a ribonucleoside 5'-triphosphate = RNA(n+1) + diphosphate
• Enzyme class 2: 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 3: E.C.3.4.22.- - ?????
• Enzyme class 4: E.C.3.6.1.15 - nucleoside-triphosphate phosphatase.
• Reaction: a ribonucleoside 5'-triphosphate + H2O = a ribonucleoside 5'-diphosphate + phosphate + H⁺
• Enzyme class 5: 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: 10.1016/j.bmcl.2013.05.037

Bioorg Med Chem Lett 23:4132-4140 (2013)

PubMed id: 23768906

Structure-based design of novel HCV NS5B thumb pocket 2 allosteric inhibitors with submicromolar gt1 replicon potency: discovery of a quinazolinone chemotype.

P.L.Beaulieu, R.Coulombe, J.Duan, G.Fazal, C.Godbout, O.Hucke, A.Jakalian, M.A.Joly, O.Lepage, M.Llinàs-Brunet, J.Naud, M.Poirier, N.Rioux, B.Thavonekham, G.Kukolj, T.A.Stammers.

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.