Published: June 07, 2011 r2011 American Chemical Society 8581 dx.doi.org/10.1021/jp202149z | J. Phys. Chem. B 2011, 115, 8581–8589 ARTICLE pubs.acs.org/JPCB Semiempirical Quantum Mechanical Method PM6-DH2X Describes the Geometry and Energetics of CK2-Inhibitor Complexes Involving Halogen Bonds Well, While the Empirical Potential Fails Petr Dobe  s, †,§ Jan  Rez  a  c, † Jind  rich Fanfrl  ik, † Michal Otyepka,* ,‡ and Pavel Hobza* ,†,‡ † Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic and Center for Biomolecules and Complex Molecular Systems, 166 10 Prague, Czech Republic ‡ Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacky University, 771 46 Olomouc, Czech Republic § Center of Molecular Biology and Gene Therapy, Department of Internal Medicine À Hematooncology, University Hospital Brno, 625 00 Brno, Czech Republic ABSTRACT: In the present study, we have investigated complexes of CK2 protein kinase with halogenated inhibitors by means of the advanced semiempirical quantum mechanical (SQM) PM6 method (called PM6-DH2X), which describes various types of noncovalent interactions including halogen bonding well. The PM6-DH2X method provides reliable geometries of those CK2 protein kinase- inhibitor complexes involving halogen bonds that agree well with the X-ray crystal structures. When the Amber empirical potential is applied, this agreement becomes considerably worse. Similarly, the binding free energies determined by the PM6-DH2X SQM method are much closer to the experimental inhibition constants than those based on the Amber empirical potential. ’ INTRODUCTION Protein kinase CK2 (formerly known also as casein kinase-2) is a pleiotropic Ser/Thr protein kinase with hundreds of regula- tion targets, which have a variety of cellular functions. CK2 plays an important role in gene-expression regulation, the synthesis and degradation of proteins, as well as the signaling and suppression of apoptosis. 1,2 CK2 is abnormally highly active in many tumor cells, 3 thus the attenuation of CK2 activity can be a strategy for the treatment of different neoplastic diseases. 4,5 CK2 is com- posed of two catalytic subunits (alpha) and two regulatory subunits (beta). 6 So far, a number of CK2 inhibitors have been described in micromolar and submicromolar ranges. 7À9 Haloge- nated benzoimidazoles belong to a widely and successfully tested family of CK2 inhibitors competing with ATP. There are a number of crystal structures available. 9À11 Of these, eight crystal structures contain aromatic tetrabromo derivatives and one a tetraiodobenzimidazole inhibitor (cf. Table 1A). 11 The inhibitors are bound to a CK2 R-catalytic subunit, specifically to a small hydrophobic cavity of the ATP binding site (Figure 1). The binding mode could explain the fairly narrow selectivity of those CK2 inhibitors. Further analysis highlights the major role of the hydrophobic effect for increasing potency within this inhibitor class. 7,12,13 It also shows that polar interactions are responsible more so for the orientation in the active site and, further, that the respective binding arises from the existence of two halogen bonds of the O 333 Br type. 12 Recently, it has been shown that novel tetraiodinated benzimidazoles 8 are more powerful inhibitors of CK2 than their tetrabrominated analogues. 11 Evidently, this class of CK2 inhibitors represents an ideal target for the study of halogen bonding in proteinÀligand complexes. A recently published survey of protein and nucleic acid structures has revealed the halogen bond as a stabilizing inter- molecular interaction. 14 Lately, some papers have even been aimed at using halogen bonding in rational drug design, 15À21 in crystal engineering, 22,23 and directing macromolecular con- formation. 24 The strength of the halogen bonding depends on its Received: March 7, 2011 Revised: May 13, 2011