Structure-based discovery of novel flavonol inhibitors of human protein kinase CK2 Andriy G. Golub • Volodymyr G. Bdzhola • Yaroslav V. Kyshenia • Vladislav M. Sapelkin • Andriy O. Prykhod’ko • Olexander P. Kukharenko • Olga V. Ostrynska • Sergiy M. Yarmoluk Received: 13 June 2011 / Accepted: 24 June 2011 / Published online: 7 July 2011 Ó Springer Science+Business Media, LLC. 2011 Abstract Serine/threonine protein kinase CK2 controls vast variety of fundamental processes in cell life; however, despite long period of study, its functional role is not completely determined. CK2 has a significant pathogenic potential and its activity is strictly associated with the development of various kinds of disorders. There are a growing number of facts that inhibitors of CK2 could be used as pharmaceutical agents for the cancer treatment, viral infections, and inflammatory diseases. In this article, we report structural and biological data on the novel syn- thetic flavonol derivatives, 3-hydroxy-4 0 -carboxyflavones, possessing a high inhibitory activity toward CK2. With the aid of combinatorial organic synthesis, molecular modeling techniques and biochemical in vitro tests, we studied the structure–activity relationships of flavonol derivatives and developed binding model describing their key intermolec- ular interactions with the CK2 ATP-binding site. Obtained data show that the synthetic 3-hydroxy-4 0 -carboxyflavones possess the highest activity among flavonol inhibitors of CK2 known till date. Keywords CK2 inhibitors Á Protein kinase Á Flavonols Á 3-hydroxy-4 0 -carboxyflavones Á Virtual screening Á Molecular dynamics Introduction ‘‘Kinome’’ is a depository of promising drug targets—pro- tein kinases, which control vast diversity of molecular interactions in cell life. Indeed, numerous reports describing the discovery of new pharmaceutical substances targeting protein kinases have been published during last few years. Some of these substances are being tested in the clinical trials, and some of them are already on the market [1]. Whereas most protein kinases are externally activated and relatively substrate-specific enzymes, there are a number of ‘‘outsider’’ kinases displaying unique bio- chemical features. An outstanding example is the protein kinase CK2—constitutively active, extremely multi-sub- strate, and pleiotropic kinase, which controls key cellular processes and has a biochemical relationship to seemingly all the signal transduction pathways [2]. Abnormally, a high constitutive activity of CK2 is suspected to underlie its pathogenic potential, and there are plenty of evidences pointing out that CK2 is the major cause of tumor and multi-drug resistance phenotype development [3–6]. The expression and activity of CK2 is enormously elevated in numerous types of tumors which leads to suppression of apoptosis and, consequently, to surviving of cancer cells even after anticancer drugs treatment. Also, it has been proven that CK2 is maintaining the life cycle of some viruses by phosphorylation of their vitally important pro- teins [7–10] In addition, it is suggested that CK2 plays a substantial role in the control of inflammatory signaling [11, 12]. Andriy G. Golub and Volodymyr G. Bdzhol contributed equally to this work. A. G. Golub (&) Á V. G. Bdzhola Á Y. V. Kyshenia Á V. M. Sapelkin Á A. O. Prykhod’ko Á O. P. Kukharenko Á O. V. Ostrynska Á S. M. Yarmoluk Institute of Molecular Biology and Genetics of National Academy of Sciences of Ukraine, 150 Zabolotnogo Str., Kyiv 03143, Ukraine e-mail: andrew.golub@gmail.com S. M. Yarmoluk Otava, Ltd., 150 Zabolotnogo Str., Kyiv 03143, Ukraine 123 Mol Cell Biochem (2011) 356:107–115 DOI 10.1007/s11010-011-0945-8