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PDBsum entry 3v3m
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Hydrolase/hydrolase inhibitor
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PDB id
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3v3m
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References listed in PDB file
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Key reference
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Title
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Discovery, Synthesis, And structure-Based optimization of a series of n-(Tert-Butyl)-2-(N-Arylamido)-2-(Pyridin-3-Yl) acetamides (ml188) as potent noncovalent small molecule inhibitors of the severe acute respiratory syndrome coronavirus (sars-Cov) 3cl protease.
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Authors
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J.Jacobs,
V.Grum-Tokars,
Y.Zhou,
M.Turlington,
S.A.Saldanha,
P.Chase,
A.Eggler,
E.S.Dawson,
Y.M.Baez-Santos,
S.Tomar,
A.M.Mielech,
S.C.Baker,
C.W.Lindsley,
P.Hodder,
A.Mesecar,
S.R.Stauffer.
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Ref.
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J Med Chem, 2013,
56,
534-546.
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PubMed id
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Abstract
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A high-throughput screen of the NIH molecular libraries sample collection and
subsequent optimization of a lead dipeptide-like series of severe acute
respiratory syndrome (SARS) main protease (3CLpro) inhibitors led to the
identification of probe compound ML188 (16-(R),
(R)-N-(4-(tert-butyl)phenyl)-N-(2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)furan-2-carboxamide,
Pubchem CID: 46897844). Unlike the majority of reported coronavirus 3CLpro
inhibitors that act via covalent modification of the enzyme, 16-(R) is a
noncovalent SARS-CoV 3CLpro inhibitor with moderate MW and good enzyme and
antiviral inhibitory activity. A multicomponent Ugi reaction was utilized to
rapidly explore structure-activity relationships within S(1'), S(1), and S(2)
enzyme binding pockets. The X-ray structure of SARS-CoV 3CLpro bound with 16-(R)
was instrumental in guiding subsequent rounds of chemistry optimization. 16-(R)
provides an excellent starting point for the further design and refinement of
3CLpro inhibitors that act by a noncovalent mechanism of action.
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