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Combined 3D-quantitative structure–activity relationships and topomer technology-based molecular design of human 4-hydroxyphenylpyruvate dioxygenase inhibitors

    Yong-Xuan Liu

    Department of Applied Chemistry, College of Arts & Sciences, Northeast Agricultural University, Harbin, 150030, China

    Authors contributed equally

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    ,
    Shuang Gao

    Department of Applied Chemistry, College of Arts & Sciences, Northeast Agricultural University, Harbin, 150030, China

    Authors contributed equally

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    ,
    Tong Ye

    Department of Applied Chemistry, College of Arts & Sciences, Northeast Agricultural University, Harbin, 150030, China

    ,
    Jia-Zhong Li

    School of Pharmacy, Lanzhou University, Lanzhou, 730000, China

    ,
    Fei Ye

    *Author for correspondence:

    E-mail Address: yefei@neau.edu.cn

    Department of Applied Chemistry, College of Arts & Sciences, Northeast Agricultural University, Harbin, 150030, China

    &
    Ying Fu

    **Author for correspondence: Tel.: +86 451 55191507;

    E-mail Address: fuying@neau.edu.cn

    Department of Applied Chemistry, College of Arts & Sciences, Northeast Agricultural University, Harbin, 150030, China

    Published Online:https://doi.org/10.4155/fmc-2019-0349

    Aim: 4-Hydroxyphenylpyruvate dioxygenase (HPPD) has attracted increasing attention as an important target against tyrosinemia type I. This paper aimed to explore the structure–activity relationship of HPPD inhibitors with pyrazole scaffolds and to design novel HPPD inhibitors. Methodology & results: The best 3D-quantitative structure–activity relationships model was established by two different strategies based on 40 pyrazole scaffold-based analogs. Screening of molecular fragments by topomer technology, combined with molecular docking, 14 structures were identified for potential human HPPD inhibitory activity. Molecular dynamics results demonstrated that all the compounds obtained bound to the enzyme and possessed a satisfactory binding free energy. Conclusion: The quantitative structure–activity relationship of HPPD inhibitors of pyrazole scaffolds was clarified and 14 original structures with potential human HPPD inhibitory activity were obtained.

    Graphical abstract

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

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