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PDBsum entry 3d62
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References listed in PDB file
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Key reference
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Title
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Development of broad-Spectrum halomethyl ketone inhibitors against coronavirus main protease 3cl(pro).
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Authors
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U.Bacha,
J.Barrila,
S.B.Gabelli,
Y.Kiso,
L.Mario amzel,
E.Freire.
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Ref.
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Chem Biol Drug Des, 2008,
72,
34-49.
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PubMed id
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Abstract
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Coronaviruses comprise a large group of RNA viruses with diverse host
specificity. The emergence of highly pathogenic strains like the SARS
coronavirus (SARS-CoV), and the discovery of two new coronaviruses, NL-63 and
HKU1, corroborates the high rate of mutation and recombination that have enabled
them to cross species barriers and infect novel hosts. For that reason, the
development of broad-spectrum antivirals that are effective against several
members of this family is highly desirable. This goal can be accomplished by
designing inhibitors against a target, such as the main protease 3CL(pro)
(M(pro)), which is highly conserved among all coronaviruses. Here 3CL(pro)
derived from the SARS-CoV was used as the primary target to identify a new class
of inhibitors containing a halomethyl ketone warhead. The compounds are highly
potent against SARS 3CL(pro) with K(i)'s as low as 300 nM. The crystal structure
of the complex of one of the compounds with 3CL(pro) indicates that this
inhibitor forms a thioether linkage between the halomethyl carbon of the warhead
and the catalytic Cys 145. Furthermore, Structure Activity Relationship (SAR)
studies of these compounds have led to the identification of a pharmacophore
that accurately defines the essential molecular features required for the high
affinity.
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