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Probing the structural requirements of A-type Aurora kinase inhibitors using 3D-QSAR and molecular docking analysis

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Abstract

Aurora-A, the most widely studied isoform of Aurora kinase overexpressed aberrantly in a wide variety of tumors, has been implicated in early mitotic entry, degradation of natural tumor suppressor p53 and centrosome maturation and separation; hence, potent inhibitors of Aurora-A may be therapeutically useful drugs in the treatment of various forms of cancer. Here, we report an in silico study on a group of 220 reported Aurora-A inhibitors with six different substructures. Three-dimensional quantitative structure–activity relationship (3D-QSAR) studies were carried out using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques on this series of molecules. The resultant optimum 3D-QSAR models exhibited an r 2cv value of 0.404-0.582 and their predictive ability was validated using an independent test set, ending in r 2pred 0.512-0.985. In addition, docking studies were employed to explore these protein–inhibitor interactions at the molecular level. The results of 3D-QSAR and docking analyses validated each other, and the key structural requirements affecting Aurora-A inhibitory activities, and the influential amino acids involved were identified. To the best of our knowledge, this is the first report on 3D-QSAR modeling of Aurora-A inhibitors, and the results can be used to accurately predict the binding affinity of related analogues and also facilitate the rational design of novel inhibitors with more potent biological activities.

A combined in silico modeling with 3D-QSAR and docking analysis was carried out on a total of 220 A-type Aurora kinase inhibitors. The results obtained from molecular docking and those from 3D-QSAR modeling can complement and validate each other very well.

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Acknowledgments

This work is supported financially by the National Natural Science Foundation of China (Grant No. 10801025) and the Fund of Northwest A&F University. We thank Dr. Ming Hao for helping with PCA analysis.

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Authors and Affiliations

  1. Center of Bioinformatics, Northwest A&F University, Yangling, Shaanxi, 712100, China

    Hui-xiao Zhang, Xia Wang & Yong-hua Wang

  2. School of Chemical Engineering, Dalian University of Technology, Dalian, Liaoning, 116012, China

    Yan Li

  3. Lab of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Graduate School of the Chinese Academy of Sciences, Dalian, Liaoning, 116023, China

    Yan Li

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  1. Hui-xiao Zhang
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  4. Yong-hua Wang
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Correspondence to Yong-hua Wang.

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Zhang, Hx., Li, Y., Wang, X. et al. Probing the structural requirements of A-type Aurora kinase inhibitors using 3D-QSAR and molecular docking analysis. J Mol Model 18, 1107–1122 (2012). https://doi.org/10.1007/s00894-011-1042-3

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  • DOI: https://doi.org/10.1007/s00894-011-1042-3

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