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PDBsum entry 5rf0
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Hydrolase/hydrolase inhibitor
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PDB id
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5rf0
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References listed in PDB file
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Key reference
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Title
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Crystallographic and electrophilic fragment screening of the sars-Cov-2 main protease.
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Authors
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A.Douangamath,
D.Fearon,
P.Gehrtz,
T.Krojer,
P.Lukacik,
C.D.Owen,
E.Resnick,
C.Strain-Damerell,
A.Aimon,
P.Ábrányi-Balogh,
J.Brandão-Neto,
A.Carbery,
G.Davison,
A.Dias,
T.D.Downes,
L.Dunnett,
M.Fairhead,
J.D.Firth,
S.P.Jones,
A.Keeley,
G.M.Keserü,
H.F.Klein,
M.P.Martin,
M.E.M.Noble,
P.O'Brien,
A.Powell,
R.N.Reddi,
R.Skyner,
M.Snee,
M.J.Waring,
C.Wild,
N.London,
F.Von delft,
M.A.Walsh.
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Ref.
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Nat Commun, 2020,
11,
5047.
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PubMed id
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Abstract
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COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no
antiviral drugs or vaccines were developed against the closely related
coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To
identify starting points for such therapeutics, we performed a large-scale
screen of electrophile and non-covalent fragments through a combined mass
spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two
cysteine viral proteases essential for viral replication. Our crystallographic
screen identified 71 hits that span the entire active site, as well as 3 hits at
the dimer interface. These structures reveal routes to rapidly develop more
potent inhibitors through merging of covalent and non-covalent fragment hits;
one series of low-reactivity, tractable covalent fragments were progressed to
discover improved binders. These combined hits offer unprecedented structural
and reactivity information for on-going structure-based drug design against
SARS-CoV-2 main protease.
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