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Insights into the c-Jun N-terminal kinase 3 (JNK3) inhibitors: CoMFA, CoMSIA analyses and molecular docking studies

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Abstract

JNK3, a protein kinase of the MAPK family that is potently activated by a variety of environmental stress and pro-inflammatory cytokines, has been recognized as an important therapeutic target for several neurodegenerative diseases. However, due to the long development cycle and the cost of R&D, no related drugs have been released. By applying the CoMFA and CoMSIA methods, QSAR models that explore the structure-activity relationship of the JNK3 inhibitors are established and validated, the parameters are satisfactory (q2 = 0.774, r2 = 0.991 for CoMFA model and q2 = 0.666, r2 = 0.990 for CoMSIA model) and base on which a series of novel molecules are designed. Molecular docking is conducted to verify the potential of the new compounds, the results shows promising activity. We speculated that the series of compounds S1–S11 might have some therapeutic activity in the c-jnk3 pathway, particularly the “S8” may prove to be the best one, which provided useful guidance for the design of new and efficient subtype selective JNK3 inhibitors.

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Acknowledgements

This work was supported by the Natural Science Foundation of China (No. 81573294, 81773593, 81872759), the Excellent Young Teachers Program of Guangdong Provincial Colleges and Universities (YQ 2015061) and the Pearl River S&T Nova Program of Guangzhou (201610010100). We thank the software support from Dr. Junxia Zheng of the Guangdong University of Technology.

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Authors and Affiliations

  1. International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, College of Pharmacy, Jinan University, Guangzhou, 510632, P. R. China

    Yanda Liu, Yuanyuan Liu, Pengcheng Wang, Jiaxi Ye, Yalun Su, Zhihong Liang, Haibo Zhou, Jun Xu & Pinghua Sun

  2. International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangdong, Guangzhou, 510006, China

    Yewei Xie & Guochao Liao

  3. International Research Center of Medicinal Administration, Peking University, Beijing, 100191, P. R. China

    Zhaohui He

  4. Faculty of Medicine and Health, the University of Sydney, Sydney, NSW, 2006, Australia

    Yiqun Chang

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  1. Yanda Liu
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  2. Yewei Xie
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  3. Yuanyuan Liu
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Correspondence to Yiqun Chang or Pinghua Sun.

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These authors contributed equally: Yanda Liu, Yewei Xie

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Liu, Y., Xie, Y., Liu, Y. et al. Insights into the c-Jun N-terminal kinase 3 (JNK3) inhibitors: CoMFA, CoMSIA analyses and molecular docking studies. Med Chem Res 28, 1796–1805 (2019). https://doi.org/10.1007/s00044-019-02416-3

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