title: Thermodynamic parameters for binding of some halogenated inhibitors of human protein kinase CK2.
abstract: 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.
authors.affiliation: Institute of Biochemistry and Biophysics PAS, Warszawa, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Winiewska
authors.affiliation: Institute of Biochemistry and Biophysics PAS, Warszawa, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Makowska
authors.affiliation: Institute of Biochemistry and Biophysics PAS, Warszawa, Poland; Nencki Institute of Experimental Biology PAS, Warszawa, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Maj
authors.affiliation: Warsaw University of Technology, Faculty of Chemistry, Warszawa, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Wielechowska
authors.affiliation: Warsaw University of Technology, Faculty of Chemistry, Warszawa, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Bretner
authors.affiliation: Institute of Biochemistry and Biophysics PAS, Warszawa, Poland. Electronic address: jarek@ibb.waw.pl.
authors.forename: Jarosław
authors.initials: J
authors.lastname: Poznański
authors.affiliation: Institute of Biochemistry and Biophysics PAS, Warszawa, Poland.
authors.forename: David
authors.initials: D
authors.lastname: Shugar
mesh_terms: D001562:Benzimidazoles / Q000737:chemistry; D001665:Binding Sites; D002151:Calorimetry; D002152:Calorimetry, Differential Scanning; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D008024:Ligands; D008745:Methylation; D008856:Microscopy, Fluorescence; D011485:Protein Binding; D055672:Static Electricity; D013696:Temperature; D013816:Thermodynamics; D014230:Triazoles / Q000737:chemistry
chemical_list: C475924:4,5,6,7-tetrabromobenzimidazole; C405354:4,5,6,7-tetrabromobenzotriazole; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D008024:Ligands; D014230:Triazoles; D047390:Casein Kinase II
keywords: Bromobenzimidazoles; Bromobenzotriazoles; DSC; Fluorescence; Halogenated protein ligands; Protein kinase CK2