Halogen Atoms in the Protein–Ligand System. Structural and Thermodynamic Studies of the Binding of Bromobenzotriazoles by the Catalytic Subunit of Human Protein Kinase CK2

• DOI: 10.1021/acs.jpcb.0c10264
• Publication Date: 2021-03-09T22:20:38Z
• Authors: Honorata Czapinska; Maria Winiewska-S...; Anna Szymaniec-Ru...; Anna Piasecka; Matthias Bochtler; Jarosław Poznański
• Keywords: Isothermal Titration Calorimetry; Halogen bond

Binding of a family brominated benzotriazoles to the catalytic subunit human protein kinase CK2 (hCK2α) was used as model system assess contribution halogen bonding protein–ligand interaction. is constitutively active pleiotropic serine/threonine that belongs CMGC group eukaryotic kinases (EPKs). Due addiction some cancer cells, an attractive and well-characterized drug target. Halogenated act ATP-competitive inhibitors with unexpectedly good selectivity for over other EPKs. We have characterized interaction bromobenzotriazoles hCK2α by X-ray crystallography, low-volume differential scanning fluorimetry, isothermal titration calorimetry. Properties free ligands in solution were additionally volumetric RT-HPLC measurements. Thermodynamic data indicate affinity increases bromo substitution, greater contributions from 5- 6-substituents than 4- 7-substituents. Except 4,7-disubstituted compounds, adopt canonical pose triazole close lysine 68, which precludes bonding. More highly substituted many additional noncanonical poses, presumably driven large hydrophobic binding. Some ligand orientations allow formation bonds hinge region. Consistent predominantly interaction, isobaric heat capacity decreases upon binding, more so higher substitution.