A competition between hydrophobic and electrostatic interactions in protein–ligand systems. Binding of heterogeneously halogenated benzotriazoles by the catalytic subunit of human protein kinase CK2

Sławomir Kasperowicz , Ewa Marzec , Agnieszka M. Maciejewska , Damian Trzybiński , Maria Bretner , Krzysztof Woźniak , Kinga Mieczkowska , J. Poznański


A series of chlorine-substituted benzotriazole derivatives, representing all possible substitution patterns of halogen atoms attached to the benzotriazole benzene ring, were synthetized as potential inhibitors of human protein kinase CK2. Basic ADME parameters for the free solutes (hydrophobicity, electronic properties) together with their binding affinity to the catalytic subunit of protein kinase CK2 were determined with reverse-phase HPLC, spectrophotometric titration, and Thermal Shift Assay Method, respectively. The analysis of position-dependent thermodynamic contribution of a chlorine atom attached to the benzotriazole ring confirmed the previous observation for brominated benzotriazoles, in which substitution at positions 5 and 6 with bromine was found crucial for ligand binding. In all tested halogenated benzotriazoles the replacement of Br with Cl decreases the hydrophobicity, while the electronic properties remain virtually unaffected. Supramolecular architecture identified in the just resolved crystal structures of three of the four possible dichloro-benzotriazoles shows how substitution distant from the triazole ring affects the pattern of intermolecular interactions. Summarizing, the benzotriazole benzene ring substitution pattern has been identified as the main driver of ligand binding, predominating the non-specific hydrophobic effect.

Author Sławomir Kasperowicz - [Institute of Biochemistry and Biophysics of the Polish Academy of Sciences]
Sławomir Kasperowicz,,
, Ewa Marzec - [Institute of Biochemistry and Biophysics of the Polish Academy of Sciences]
Ewa Marzec,,
, Agnieszka M. Maciejewska
Agnieszka M. Maciejewska,,
, Damian Trzybiński - [University of Warsaw, Biological and Chemical Research Centre]
Damian Trzybiński,,
, Maria Bretner (FC / CDSB)
Maria Bretner,,
- Chair of Drug and Cosmetics Biotechnology
, Krzysztof Woźniak
Krzysztof Woźniak,,
, Kinga Mieczkowska - [Institute of Biochemistry and Biophysics of the Polish Academy of Sciences]
Kinga Mieczkowska,,
, J. Poznański
J. Poznański,,
Journal seriesIUBMB Life, ISSN 1521-6543, e-ISSN 1521-6551
Issue year2020
Publication size in sheets0.5
Keywords in English bromobenzotriazoles chlorobenzotriazoles chromatographic hydrophobicity index crystal structure halogenated benzotriazoles human protein kinase CK2 thermal shift assay
ASJC Classification1303 Biochemistry; 1307 Cell Biology; 1308 Clinical Biochemistry; 1311 Genetics; 1312 Molecular Biology
URL https://iubmb.onlinelibrary.wiley.com/doi/full/10.1002/iub.2271
Languageen angielski
iub.2271.pdf 4.23 MB
Score (nominal)100
Score sourcejournalList
ScoreMinisterial score = 100.0, 03-08-2020, ArticleFromJournal
Publication indicators Scopus Citations = 0; Scopus SNIP (Source Normalised Impact per Paper): 2018 = 0.859; WoS Impact Factor: 2018 = 3.051 (2) - 2018=3.39 (5)
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