It may be concluded that the balance of hydrophobic and electrostatic interactions are the main forces Deguelin driving the binding of brominated benzotriazoles to CK2a. The dominant effect of permutation of bromination sites simply suggests that a decrease in halogenation of known multiple halogenated inhibitors may result in significant enhancement of their activity. However, it should be noted that enzymatic dehalogenation may possibly occur in vivo, as demonstrated for reductive dehalogenation of polyhalogenated phenols and haloalkanes by bacteria, or iodotyrosine metabolism in mammals. Structural studies of CK2a-ligand complexes show numerous hydrophobic contacts, demonstrating that hydrophobic inhibitors are favored. Moreover, unfavorable hydrophobic solvation moves the protein-ligand equilibrium towards the bound state. But the increase in drug hydrophobicity is limited by the AMG 853 minimal solubility required for drug administration. For TBBt, which is very poorly soluble in its neutral form, addition of DMSO is required, even for biochemical studies, in which a final 2% DMSO concentration was used. Solubilities of two identified good inhibitors, 5,6-Br2Bt and 4,5,6-Br3Bt, were found to be as low as for TBBt at neutral pH, and visibly higher in acidic solution. However, there are alternative approaches for administration of such hydrophobic compounds, based on formation of water-soluble supramolecular complexes of drugs with carrier molecules. These include cyclodextrins of an appropriate size or some calix- -arenes. It should also be noted that 5,6-Br2Bt is almost neutral at physiological pH, which may eventually result in a significant decrease of the undesired side effect of ribosome depolarization observed for TBBt, which is anionic in physiological conditions. Finally, we direct attention to the fact that there are numerous reports on inhibition of various protein kinases by halogenated benzotriazoles and benzimidazoles, and their nucleosides, for some of which the site of halogenation were not unequivocally identified. The present series of well-defined halogeno benzotriazoles should prove useful in more comprehensive studies on inhibition of kinases other than CK2, and suggest, furthermore, that it would be desirable to synthesize the corresponding series of halogeno benzimidazoles. Docking was performed with the aid of the Autodock program implemented in the Yasara-model package. Interactions between ligands and the protein were scored by Van der Waals, electrostatic, hydrogen bonding and desolvation energy terms adopted from the Amber03 force field. The docking procedure for location of ligands was performed in a space restricted from the reference location of TBBt in its crystal structure with CK2a. Taking into account the N- protomeric equilibrium for neutral asymmetric molecules, all 16 possible permutations of H substitutions were analyzed.