TY - JOUR
T1 - Relative role of halogen bonds and hydrophobic interactions in inhibition of human protein kinase CK2α by tetrabromobenzotriazole and some C(5)-substituted analogues
AU - Wãsik, Romualda
AU - Łebska, Maja
AU - Felczak, Krzysztof
AU - Poznański, Jarosław
AU - Shugar, David
PY - 2010/8/19
Y1 - 2010/8/19
N2 - To examine the relative role of halogen bonding and hydrophobic interactions in the inhibition of human CK2α by 4,5,6,7- tetrabromobenzotriazole (TBBt), we have synthesized a series of 5-substituted benzotriazoles (Bt) and the corresponding 5-substituted 4,6,7- tribromobenzotriazoles (Br3Bt) and examined their inhibition of human CK2α relative to that of TBBt. The various C(5) substituents differ in size (H and CH3), electronegativity (NH2 and NO 2), and hydrophobicity (COOH and Cl). Some substituents were halogen bond donors (Cl, Br), while others were fluorine bond donors (F and CF 3). Most of the 5-substituted analogues of Br3Bt (with the exception of COOH and NH2) exhibited inhibitory activity comparable to that of TBBt, whereas the 5-substituted analogues of the parent Bt were only weakly active (Br, Cl, NO2, CF3) or inactive. The observed effect of the volume of a ligand molecule pointed to its predominant role in inhibitory activity, indicating that presumed halogen bonding, identified in crystal structures and by molecular modeling, is dominated by hydrophobic interactions. Extended QSAR analysis additionally pointed to the monoanion and a preference for the N(1)-H protomer of the neutral ligand as parameters crucial for prediction of inhibitory activity. This suggests that the monoanions of TBBt and its congeners are the active forms that efficiently bind to CK2α, and the binding affinity is coupled with protomeric equilibrium of the neutral ligand.
AB - To examine the relative role of halogen bonding and hydrophobic interactions in the inhibition of human CK2α by 4,5,6,7- tetrabromobenzotriazole (TBBt), we have synthesized a series of 5-substituted benzotriazoles (Bt) and the corresponding 5-substituted 4,6,7- tribromobenzotriazoles (Br3Bt) and examined their inhibition of human CK2α relative to that of TBBt. The various C(5) substituents differ in size (H and CH3), electronegativity (NH2 and NO 2), and hydrophobicity (COOH and Cl). Some substituents were halogen bond donors (Cl, Br), while others were fluorine bond donors (F and CF 3). Most of the 5-substituted analogues of Br3Bt (with the exception of COOH and NH2) exhibited inhibitory activity comparable to that of TBBt, whereas the 5-substituted analogues of the parent Bt were only weakly active (Br, Cl, NO2, CF3) or inactive. The observed effect of the volume of a ligand molecule pointed to its predominant role in inhibitory activity, indicating that presumed halogen bonding, identified in crystal structures and by molecular modeling, is dominated by hydrophobic interactions. Extended QSAR analysis additionally pointed to the monoanion and a preference for the N(1)-H protomer of the neutral ligand as parameters crucial for prediction of inhibitory activity. This suggests that the monoanions of TBBt and its congeners are the active forms that efficiently bind to CK2α, and the binding affinity is coupled with protomeric equilibrium of the neutral ligand.
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U2 - 10.1021/jp102848y
DO - 10.1021/jp102848y
M3 - Article
C2 - 20734498
AN - SCOPUS:77955567154
SN - 1520-6106
VL - 114
SP - 10601
EP - 10611
JO - Journal of Physical Chemistry B
JF - Journal of Physical Chemistry B
IS - 32
ER -