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Molecules 2017, 22(5), 840; doi:10.3390/molecules22050840

Exploring the Pivotal Role of the CK2 Hinge Region Sub-Pocket in Binding with Tricyclic Quinolone Analogues by Computational Analysis

1
National Engineering Laboratory for Advanced Municipal Wastewater Treatment and Reuse Technology, Engineering Research Center of Beijing, Beijing University of Technology, Beijing 100124, China
2
Beijing Key Laboratory of Environmental & Viral Oncology, College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, China
*
Authors to whom correspondence should be addressed.
Academic Editor: F. Javier Luque
Received: 14 April 2017 / Revised: 12 May 2017 / Accepted: 17 May 2017 / Published: 19 May 2017
(This article belongs to the Special Issue Frontiers in Computational Chemistry for Drug Discovery)
View Full-Text   |   Download PDF [2453 KB, uploaded 19 May 2017]   |  

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. View Full-Text
Keywords: protein kinase CK2; inhibitor; fragment-based design; tricyclic quinoline compounds; pharmacophore group protein kinase CK2; inhibitor; fragment-based design; tricyclic quinoline compounds; pharmacophore group
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Zhou, Y.; Zhang, N.; Tang, S.; Qi, X.; Zhao, L.; Zhong, R.; Peng, Y. Exploring the Pivotal Role of the CK2 Hinge Region Sub-Pocket in Binding with Tricyclic Quinolone Analogues by Computational Analysis. Molecules 2017, 22, 840.

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