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PDBsum entry 4jjs
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Transferase/transferase inhibitor
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PDB id
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4jjs
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References listed in PDB file
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Key reference
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Title
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Structure-Based design of novel hcv ns5b thumb pocket 2 allosteric inhibitors with submicromolar gt1 replicon potency: discovery of a quinazolinone chemotype.
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Authors
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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.
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Ref.
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Bioorg Med Chem Lett, 2013,
23,
4132-4140.
[DOI no: ]
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PubMed id
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Abstract
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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.
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