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Thermodynamic parameters for binding of some halogenated inhibitors of human protein kinase CK2.

Winiewska, Maria and Makowska, Małgorzata and Maj, Piotr and Wielechowska, Monika and Bretner, Maria and Poznański, Jarosław and Shugar, David (2015) Thermodynamic parameters for binding of some halogenated inhibitors of human protein kinase CK2. Biochemical and biophysical research communications, 456 (1). pp. 282-287. ISSN 1090-2104

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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.

Item Type:Article
Subjects:Q Science > Q Science (General)
Divisions:Department of Biophysics
ID Code:882
Deposited By: Prof Jaroslaw Poznanski
Deposited On:07 Jan 2015 12:12
Last Modified:07 Jan 2015 12:12

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