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PDBsum entry 3mj5
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Viral protein
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PDB id
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3mj5
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References listed in PDB file
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Key reference
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Title
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Severe acute respiratory syndrome coronavirus papain-Like novel protease inhibitors: design, Synthesis, Protein-Ligand X-Ray structure and biological evaluation.
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Authors
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A.K.Ghosh,
J.Takayama,
K.V.Rao,
K.Ratia,
R.Chaudhuri,
D.C.Mulhearn,
H.Lee,
D.B.Nichols,
S.Baliji,
S.C.Baker,
M.E.Johnson,
A.D.Mesecar.
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Ref.
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J Med Chem, 2010,
53,
4968-4979.
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PubMed id
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Abstract
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The design, synthesis, X-ray crystal structure, molecular modeling, and
biological evaluation of a series of new generation SARS-CoV PLpro inhibitors
are described. A new lead compound 3 (6577871) was identified via
high-throughput screening of a diverse chemical library. Subsequently, we
carried out lead optimization and structure-activity studies to provide a series
of improved inhibitors that show potent PLpro inhibition and antiviral activity
against SARS-CoV infected Vero E6 cells. Interestingly, the (S)-Me inhibitor 15
h (enzyme IC(50) = 0.56 microM; antiviral EC(50) = 9.1 microM) and the
corresponding (R)-Me 15 g (IC(50) = 0.32 microM; antiviral EC(50) = 9.1 microM)
are the most potent compounds in this series, with nearly equivalent enzymatic
inhibition and antiviral activity. A protein-ligand X-ray structure of 15
g-bound SARS-CoV PLpro and a corresponding model of 15 h docked to PLpro provide
intriguing molecular insight into the ligand-binding site interactions.
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