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PDBsum entry 2br1
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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 chk1 inhibitors: insights into hydrogen bonding and protein-Ligand affinity.
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Authors
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N.Foloppe,
L.M.Fisher,
R.Howes,
P.Kierstan,
A.Potter,
A.G.Robertson,
A.E.Surgenor.
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Ref.
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J Med Chem, 2005,
48,
4332-4345.
[DOI no: ]
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PubMed id
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Abstract
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We report the discovery, synthesis, and crystallographic binding mode of novel
furanopyrimidine and pyrrolopyrimidine inhibitors of the Chk1 kinase, an
oncology target. These inhibitors are synthetically tractable and inhibit Chk1
by competing for its ATP site. A chronological account allows an objective
comparison of modeled compound docking modes to the subsequently obtained
crystal structures. The comparison provides insights regarding the
interpretation of modeling results, in relationship to the multiple reasonable
docking modes which may be obtained in a kinase-ATP site. The crystal structures
were used to guide medicinal chemistry efforts. This led to a thorough
characterization of a pair of ligand-protein complexes which differ by a single
hydrogen bond. An analysis indicates that this hydrogen bond is expected to
contribute a fraction of the 10-fold change in binding affinity, adding a
valuable observation to the debate about the energetic role of hydrogen bonding
in molecular recognition.
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