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PDBsum entry 4tyd
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PDB id:
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Hydrolase
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Title:
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Structure-based design of a novel series of azetidine inhibitors of the hepatitis c virus ns3/4a serine protease
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Structure:
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Ns3 protease. Chain: a, b, c, d, e, f, g, h, j, k, l, m. Engineered: yes
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Source:
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Hepatitis c virus (isolate 1). Organism_taxid: 11104. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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2.84Å
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R-factor:
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0.222
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R-free:
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0.267
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Authors:
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C.Parsy
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Key ref:
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C.Parsy
et al.
(2014).
Structure-based design of a novel series of azetidine inhibitors of the hepatitis C virus NS3/4A serine protease.
Bioorg Med Chem Lett,
24,
4444-4449.
PubMed id:
DOI:
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Date:
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08-Jul-14
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Release date:
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10-Sep-14
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PROCHECK
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Headers
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References
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Q0ZNA6
(Q0ZNA6_9HEPC) -
NS3 protease (Fragment) from Hepacivirus hominis
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Seq:
Struc:
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181 a.a.
194 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 2 residue positions (black
crosses)
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Enzyme class:
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E.C.3.6.4.13
- Rna helicase.
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Reaction:
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ATP + H2O = ADP + phosphate + H+
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ATP
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+
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H2O
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=
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ADP
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+
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phosphate
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Bioorg Med Chem Lett
24:4444-4449
(2014)
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PubMed id:
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Structure-based design of a novel series of azetidine inhibitors of the hepatitis C virus NS3/4A serine protease.
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C.Parsy,
F.R.Alexandre,
G.Brandt,
C.Caillet,
S.Cappelle,
D.Chaves,
T.Convard,
M.Derock,
D.Gloux,
Y.Griffon,
L.Lallos,
F.Leroy,
M.Liuzzi,
A.G.Loi,
L.Moulat,
C.Musiu,
H.Rahali,
V.Roques,
M.Seifer,
D.Standring,
D.Surleraux.
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ABSTRACT
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Structural homology between thrombin inhibitors and the early tetrapeptide HCV
protease inhibitor led to the bioisosteric replacement of the P2 proline by a
2,4-disubstituted azetidine within the macrocyclic β-strand mimic. Molecular
modeling guided the design of the series. This approach was validated by the
excellent activity and selectivity in biochemical and cell based assays of this
novel series and confirmed by the co-crystal structure of the inhibitor with the
NS3/4A protein (PDB code: 4TYD).
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