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Int. J. Mol. Sci. 2011, 12(10), 7004-7021; doi:10.3390/ijms12107004

Structural Determinants of CX-4945 Derivatives as Protein Kinase CK2 Inhibitors: A Computational Study

1
Chemistry and Chemical Engineering School, Northeast Petroleum University, Daqing 163000, China
2
Center of Bioinformatics, Northwest A&F University, Yangling 712100, Shaanxi, China
3
Department of Materials Sciences and Chemical Engineering, Dalian University of Technology, Dalian 116023, Liaoning, China
4
Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Graduate School of the Chinese Academy of Sciences, Dalian 116023, Liaoning, China
5
Laboratory of Molecular Modeling and Design, Dalian Institute of Chemical Physics, Graduate School of the Chinese Academy of Sciences, Dalian 116023, Liaoning, China
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 17 August 2011 / Revised: 16 September 2011 / Accepted: 11 October 2011 / Published: 20 October 2011
(This article belongs to the Section Physical Chemistry, Theoretical and Computational Chemistry)

Abstract

Protein kinase CK2, also known as casein kinase-2, is involved in a broad range of physiological events including cell growth, proliferation and suppression of apoptosis which are related to human cancers. A series of compounds were identified as CK2 inhibitors and their inhibitory activities varied depending on their structures. In order to explore the structure-activity correlation of CX-4945 derivatives as inhibitors of CK2, in the present study, a set of ligand- and receptor-based 3D-QSAR models were developed employing Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA). The optimum CoMFA (Rcv2 = 0.618, Rpred2 = 0.892) and CoMSIA (Rcv2 = 0.681, Rpred2 = 0.843) models exhibited reasonable statistical characteristics for CX-4945 derivatives. The results indicated that electrostatic effects contributed the most to both CoMFA and CoMSIA models. The combination of docking analysis and molecular dynamics (MD) simulation showed that Leu45, Lys68, Glu81, Val116, Asp175 and Trp176 of CK2 which formed several direct or water-bridged H-bonds with CX-4945 are crucial for CX-4945 derivatives recognition to CK2. These results can offer useful theoretical references for designing more potent CK2 inhibitors.
Keywords: CK2 inhibitors; 3D-QSAR; molecular docking; molecular dynamics CK2 inhibitors; 3D-QSAR; molecular docking; molecular dynamics
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Liu, H.; Wang, X.; Wang, J.; Wang, J.; Li, Y.; Yang, L.; Li, G. Structural Determinants of CX-4945 Derivatives as Protein Kinase CK2 Inhibitors: A Computational Study. Int. J. Mol. Sci. 2011, 12, 7004-7021.

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