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

Winiewska, Maria; Makowska, Małgorzata; Maj, Piotr; Wielechowska, Monika; Bretner, Maria; Poznański, Jarosław; Shugar, David

doi:10.1016/j.bbrc.2014.11.072

Cited by 16 publications

(24 citation statements)

References 37 publications

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“…The preference toward 5,6‐dihalogenated ligands seems to favor the halogen bonds formed between the hinge region of hCK2α and benzotriazole derivative, as has been observed for TBBz . Finally, only a weak correlation between ligand pK a and ∆ T m was found, clearly confirming that nonspecific hydrophobic effect predominates any specific electrostatic interactions.…”

Section: Resultssupporting

confidence: 55%

Thermodynamic contribution of iodine atom to the binding of heterogeneously polyhalogenated benzotriazoles by the catalytic subunit of human protein kinase CK2

2020

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A series of novel benzotriazole derivatives containing iodine atom(s) were synthesized. The binding of these compounds to the catalytic subunit of human protein kinase CK2 was evaluated using differential scanning fluorimetry. The obtained thermodynamic data were compared with those determined previously for the brominated and chlorinated benzotriazole analogues to get a deeper insight into the thermodynamic contribution of iodine substitution to the free energy of ligand binding. We have shown that iodine atom(s) attached to the benzene ring of benzotriazole enhance(s) its binding by the target protein. This effect is the strongest when two iodine atoms are attached at positions peripheral to the triazole ring, which according to the structures deposited in protein data bank may be indicative for the formation of the halogen bond between iodine and carbonyl groups of residues located in the hinge region of the protein. Finally, quantitative structure-activity relationship analysis pointed the solute hydrophobicity as the main factor contributing to the binding affinity. K E Y W O R D S differential scanning fluorimetry, halogen bonding, halogenated benzotirazoles, iodinated benzotirazoles, protein kinase CK2, protein-ligand interactions.

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Section: Resultssupporting

confidence: 55%

Thermodynamic contribution of iodine atom to the binding of heterogeneously polyhalogenated benzotriazoles by the catalytic subunit of human protein kinase CK2

2020

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“…Furthermore, the moderate inhibitory activity exhibited by 4,5,6,7-tetramethylbenzotriazole (Zien et al, 2003), which in contrast to TBBt is in the neutral form at physiological pH (Poznanski et al, 2007), again points to a balance of electrostatic and hydrophobic interactions as an important factor contributing to CK2α inhibition. Accordingly, recent DSC-derived thermodynamic data for binding of TBBt, TBBz and their close structural analogues to CK2α (Winiewska et al, 2015a;Winiewska et al, 2015b) confirm the predominant contribution of electrostatic and hydrophobic interactions. For ligands that are mostly dissociated (i.e.…”

Section: Electrostatic Contribution To Ligand Bindingmentioning

confidence: 84%

Halogen bonds involved in binding of halogenated ligands by protein kinases.

et al. 2016

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Analysis of 664 known structures of protein kinase complexes with halogenated ligands revealed 424 short contacts between a halogen atom and a potential protein X-bond acceptor, the topology and geometry of which were analyzed according to the type of a halogen atom (X = Cl, Br, I) and a putative protein X-bond acceptor. Among 236 identified halogen bonds, the most represented ones are directed to backbone carbonyls of the hinge region and may replace the pattern of ATP-like hydrogen bonds. Some halogen-π interactions with either aromatic residues or peptide bonds, that accompany the interaction with the hinge region, may possibly enhance ligand selectivity. Interestingly, many of these halogen-π interactions are bifurcated. Geometrical preferences identify iodine as the strongest X-bond donor, less so bromine, while virtually no such preferences were observed for chlorine; and a backbone carbonyl as the strongest X-bond acceptor. The presence of a halogen atom in a ligand additionally affects the properties of proximal hydrogen bonds, which according to geometrical parameters get strengthened, when a nitrogen of a halogenated ligand acts as the hydrogen bond donor.

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“…In some cases the procedures were further optimized (see Supplementary Materials for details). bromination [79], followed by reductive sulfur extrusion [81] and diazotization with NaNO 2 [63].…”

Section: Synthetic Proceduresmentioning

confidence: 99%

“…5-Bromo-1H-benzotriazole (5-BrBt) was prepared from 4-bromo-o-phenylenediamine by diazotization with NaNO 2 [63]. 4,5-Dibromo-1H-benzotriazole (4,5-Br 2 Bt) was prepared by bromination of commercially available 5-bromo-2,1,3-benzothiadiazole [79], followed by reductive sulfur extrusion [81] and diazotization [63].…”

Section: Synthetic Proceduresmentioning

confidence: 99%

“…Analysis of a series of nine benzotriazoles brominated on the benzene ring clearly showed that their inhibitory activity against CK2α is strongly correlated with their physico-chemical properties (aqueous solubility, molecular volume, pK a for dissociation of the triazole proton) [60,61]. We have also shown that a balance of hydrophobic and electrostatic interactions, with an eventual possible contribution of halogen bonding, drive inhibitory activities of benzotriazoles halogenated on the benzene ring [60][61][62][63].…”

Section: Introductionmentioning

confidence: 99%

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Thermodynamics parameters for binding of halogenated benzotriazole inhibitors of human protein kinase CK2α

Winiewska

Kucińska

Makowska

et al. 2015

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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The interaction of human CK2α (hCK2α) with nine halogenated benzotriazoles, TBBt and its analogues representing all possible patterns of halogenation on the benzene ring of benzotriazole, was studied by biophysical methods. Thermal stability of protein-ligand complexes, monitored by calorimetric (DSC) and optical (DSF) methods, showed that the increase in the mid-point temperature for unfolding of protein-ligand complexes (i.e. potency of ligand binding to hCK2α) follow the inhibitory activities determined by biochemical assays. The dissociation constant for the ATP-hCK2α complex was estimated with the aid of microscale thermophoresis (MST) as 4.3±1.8 μM, and MST-derived dissociation constants determined for halogenated benzotriazoles, when converted according to known ATP concentrations, perfectly reconstruct IC50 values determined by the biochemical assays. Ligand-dependent quenching of tyrosine fluorescence, together with molecular modeling and DSC-derived heats of unfolding, support the hypothesis that halogenated benzotriazoles bind in at least two alternative orientations, and those that are efficient hCK2α inhibitors bind in the orientation which TBBt adopts in its complex with maize CK2α. DSC-derived apparent heat for ligand binding (ΔΔHbind) is driven by intermolecular electrostatic interactions between Lys68 and the triazole ring of the ligand, as indicated by a good correlation between ΔΔHbind and ligand pKa. Overall results, additionally supported by molecular modeling, confirm that a balance of hydrophobic and electrostatic interactions contribute predominantly (~40 kJ/mol), relative to possible intermolecular halogen/hydrogen bonding (less than 10 kJ/mol), in binding of halogenated benzotriazoles to the ATP-binding site of hCK2α. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases.

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

Cited by 16 publications

References 37 publications

Thermodynamic contribution of iodine atom to the binding of heterogeneously polyhalogenated benzotriazoles by the catalytic subunit of human protein kinase CK2

Thermodynamic contribution of iodine atom to the binding of heterogeneously polyhalogenated benzotriazoles by the catalytic subunit of human protein kinase CK2

Halogen bonds involved in binding of halogenated ligands by protein kinases.

Thermodynamics parameters for binding of halogenated benzotriazole inhibitors of human protein kinase CK2α

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