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PDBsum entry 4oks
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Hydrolase/hydrolase inhibitor
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PDB id
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4oks
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References listed in PDB file
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Key reference
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Title
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Integrated strategies for identifying leads that target the ns3 helicase of the hepatitis c virus.
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Authors
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S.R.Laplante,
A.K.Padyana,
A.Abeywardane,
P.Bonneau,
M.Cartier,
R.Coulombe,
A.Jakalian,
J.Wildeson-Jones,
X.Li,
S.Liang,
G.Mckercher,
P.White,
Q.Zhang,
S.J.Taylor.
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Ref.
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J Med Chem, 2014,
57,
2074-2090.
[DOI no: ]
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PubMed id
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Abstract
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Future treatments for individuals infected by the hepatitis C virus (HCV) will
likely involve combinations of compounds that inhibit multiple viral targets.
The helicase of HCV is an attractive target with no known drug candidates in
clinical trials. Herein we describe an integrated strategy for identifying
fragment inhibitors using structural and biophysical techniques. Based on an
X-ray structure of apo HCV helicase and in silico and bioinformatic analyses of
HCV variants, we identified that one site in particular (labeled 3 + 4) was the
most conserved and attractive pocket to target for a drug discovery campaign.
Compounds from multiple sources were screened to identify inhibitors or binders
to this site, and enzymatic and biophysical assays (NMR and SPR) were used to
triage the most promising ligands for 3D structure determination by X-ray
crystallography. Medicinal chemistry and biophysical evaluations focused on
exploring the most promising lead series. The strategies employed here can have
general utility in drug discovery.
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