Abstract
Protein kinase CK2 has been considered as an attractive therapeutic target of cancer therapy. The tricyclic quinoline compound CX-4945 is the first representative of CK2 inhibitors used in human clinical trials. The binding of non-2,6-naphtyridine substituted compounds 27e (IC50 > 500 nM) and 27h (IC50 > 1000 nM) to CK2 is abolished. However, the unbinding mechanisms due to the key pharmacophore group replacement of compounds 27e and 27h are unveiled. In the present work, combined computational analysis was performed to investigate the underlying structural basis of the low-affinity of two systems. As indicated in the results, the loss of hydrogen bonds between the non-2,6-naphtyridine and the hinge region destroyed the proper recognition of the two complexes. Besides, the allosteric mechanisms between the deviated ligands and the changed regions (G-loop, C-loop and β4/β5 loop) are proposed. Furthermore, energetic analysis was evaluated by detailed energy calculation and residue-based energy decomposition. More importantly, the summary of known polar pharmacophore groups elucidates the pivotal roles of hinge region sub-pocket in the binding of CK2 inhibitors. These results provide rational clues to the fragment-based design of more potent CK2 inhibitors.
Highlights
Protein kinase CK2, known as casein kinase II, is a ubiquitous eukaryotic serine/threonine protein kinase [1,2]
Molecular dynamics simulations and energy analysis were employed to explore the pivotal roles of the hinge region sub-pocket in the binding of tricyclic quinolone analogues with CK2
The loss of H-bonds between non-2,6-naphtyridine substituent compounds and the hinge region induce the reorientation of the compound
Summary
Protein kinase CK2, known as casein kinase II, is a ubiquitous eukaryotic serine/threonine protein kinase [1,2]. The stable heterotetramers assembled by catalytic (α) and regulatory subunits (β) catalyze the phosphorylation of over 300 known substrates involved in important cellular processes [3,4]. Most substrates are transcription factors or regulatory proteins, by which CK2 is implicated in signal transduction pathways associated with human diseases [5,6]. CK2α is considered as a potential therapeutic antitumor target, and the discovery of ATP-competitive inhibitors has been the focus of anti-cancer drug design. Numerous efforts have been made to design and synthesize a series of ATP-competitive inhibitors, including polyhalogenated benzimidazole derivatives [9,10], Molecules 2017, 22, 840; doi:10.3390/molecules22050840 www.mdpi.com/journal/molecules
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
