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3D-QSAR modeling and molecular docking study on Mer kinase inhibitors of pyridine-substituted pyrimidines

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Abstract

Mer kinase is a novel therapeutic target for many cancers, and overexpression of Mer receptor tyrosine kinase has been observed in several kinds of tumors. To deeply understand the structure–activity correlation of a series of pyridine/pyrimidine analogs as potent Mer inhibitors, a combined molecular docking and three-dimensional quantitative structure–activity relationship modeling was carried out. A comparative molecular similarity indices analysis model was developed based on the maximum common substructure alignment. The optimum model exhibited statistically significant results: the cross-validated correlation coefficient \(q^{2}\) was 0.599, and non-cross-validated \(r^{2}\) value was 0.984. Furthermore, the results of internal validation such as bootstrapping, Y-randomization as well as external validation (the external predictive correlation coefficient \(r_\mathrm{ext}^2 =0.728)\) confirmed the rationality and good predictive ability of the model. Using the crystal structure of Mer kinase, the selected pyridine/pyrimidine compounds were docked into the enzyme active site. Some key amino acid residues were determined, and hydrogen bonding and hydrophobic interactions between Mer kinase and inhibitors were identified. The satisfactory results from this study may aid in the research and development of novel potent Mer kinase inhibitors.

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Acknowledgments

This work was supported by the Science and Technology Development Project of Shandong Province: No. 2012YD18038 and No. 2012YD18042.

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Authors and Affiliations

  1. Department of Oncology, The Affiliated Hospital of Medical College Qingdao University, Qingdao University, Qingdao, 266071, Shandong, China

    Zhuang Yu

  2. Department of Pharmacy, Qingdao University, Qingdao, 266071, Shandong, China

    Xianchao Li, Cuizhu Ge & Hua Gao

  3. Laboratory of New Fibrous Materials and Modern Textile, The Growing Base for State Key Laboratory, Department of Pharmacy, Institute for Computational Science and Engineering, Qingdao University, Qingdao, 266071, Shandong, China

    Hongzong Si & Yunbo Duan

  4. The School of Public Health, Qingdao University, Qingdao, 266071, Shandong, China

    Lianhua Cui

  5. Department of Chemistry, Lanzhou University, Lanzhou, 730000, Gansu, China

    Honglin Zhai

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  1. Zhuang Yu
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Yu, Z., Li, X., Ge, C. et al. 3D-QSAR modeling and molecular docking study on Mer kinase inhibitors of pyridine-substituted pyrimidines. Mol Divers 19, 135–147 (2015). https://doi.org/10.1007/s11030-014-9556-0

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