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Title
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Thermodynamic parameters for binding of some halogenated inhibitors of human protein kinase CK2.
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Authors
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M.Winiewska,
M.Makowska,
P.Maj,
M.Wielechowska,
M.Bretner,
J.Poznański,
D.Shugar.
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Ref.
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Biochem Biophys Res Commun, 2015,
456,
282-287.
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PubMed id
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Abstract
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The interaction of human CK2α with a series of tetrabromobenzotriazole (TBBt)
and tetrabromobenzimidazole (TBBz) analogs, in which one of the bromine atoms
proximal to the triazole/imidazole ring is replaced by a methyl group, was
studied by biochemical (IC50) and biophysical methods (thermal stability of
protein-ligand complex monitored by DSC and fluorescence). Two newly synthesized
tri-bromo derivatives display inhibitory activity comparable to that of the
reference compounds, TBBt and TBBz, respectively. DSC analysis of the stability
of protein-ligand complexes shows that the heat of ligand binding (Hbind) is
driven by intermolecular electrostatic interactions involving the
triazole/imidazole ring, as indicated by a strong correlation between Hbind and
ligand pKa. Screening, based on fluorescence-monitored thermal unfolding of
protein-ligand complexes, gave comparable results, clearly identifying ligands
that most strongly bind to the protein. Overall results, additionally supported
by molecular modeling, confirm that a balance of hydrophobic and electrostatic
interactions contribute predominantly, relative to possible intermolecular
halogen bonding, in binding of the ligands to the CK2α ATP-binding site.
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