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PDBsum entry 2c3j
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References listed in PDB file
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Key reference
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Title
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Identification of a buried pocket for potent and selective inhibition of chk1: prediction and verification.
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Authors
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N.Foloppe,
L.M.Fisher,
G.Francis,
R.Howes,
P.Kierstan,
A.Potter.
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Ref.
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Bioorg Med Chem Lett, 2006,
14,
1792-1804.
[DOI no: ]
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PubMed id
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Abstract
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Inhibition of the Chk1 kinase by small molecules binding to its active site is a
strategy of great therapeutic interest for oncology. We report how computational
modelling predicted the binding mode of ligands of special interest to the Chk1
ATP site, for representatives of an indazole series and debromohymenialdisine.
These binding modes were subsequently confirmed by X-ray crystallography. The
binding mode of a potent indazole derivative involves non-conventional C-H...O
and N-H...pi-aromatic interactions with the protein. These interactions are
formed in a buried pocket at the periphery of the ATP-binding site, the
importance of which has previously been overlooked for ligand design against
Chk1. It is demonstrated that filling this pocket can confer ligands with
dramatically enhanced affinity for Chk1. Structural arguments in conjunction
with assay data explain why targeting this pocket is also advantageous for
selective binding to Chk1. Structural overlays of known inhibitors complexed
with Chk1 show that only the indazole series utilizes the pocket of interest.
Therefore, the analysis presented here should prove helpful in guiding future
structure-based ligand design efforts against Chk1.
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