title: Inhibition of protein kinase CK2 by anthraquinone-related compounds. A structural insight.
abstract: Protein kinases play key roles in signal transduction and therefore are among the most attractive targets for drug design. The pharmacological aptitude of protein kinase inhibitors is highlighted by the observation that various diseases with special reference to cancer are because of the abnormal expression/activity of individual kinases. The resolution of the three-dimensional structure of the target kinase in complex with inhibitors is often the starting point for the rational design of this kind of drugs, some of which are already in advanced clinical trial or even in clinical practice. Here we present and discuss three new crystal structures of ATP site-directed inhibitors in complex with "casein kinase-2" (CK2), a constitutively active protein kinase implicated in a variety of cellular functions and misfunctions. With the help of theoretical calculations, we disclose some key features underlying the inhibitory efficiency of anthraquinone derivatives, outlining three different binding modes into the active site. In particular, we show that a nitro group in a hydroxyanthraquinone scaffold decreases the inhibitory constants K(i) because of electron-withdrawing and resonance effects that enhance the polarization of hydroxylic substituents in paraposition.
authors.affiliation: Department of Organic Chemistry, University of Padova, Padova 35131, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: De Moliner
authors.forename: Stefano
authors.initials: S
authors.lastname: Moro
authors.forename: Stefania
authors.initials: S
authors.lastname: Sarno
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zagotto
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zanotti
authors.forename: Lorenzo A
authors.initials: LA
authors.lastname: Pinna
authors.forename: Roberto
authors.initials: R
authors.lastname: Battistutta
mesh_terms: D000880:Anthraquinones / Q000494:pharmacology*; D047390:Casein Kinase II; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008958:Models, Molecular; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D003313:Zea mays / Q000201:enzymology
chemical_list: D000880:Anthraquinones; D004791:Enzyme Inhibitors; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases