Design and Synthesis of Imidazolidine-2,4-Dione Derivatives as Selective Inhibitors by Targeting Protein Tyrosine Phosphatase-1B Over T-Cell Protein Tyrosine Phosphatase

Authors

  • Ying Ma,

    1. Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, China
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    • The authors contributed equally to this work.

  • Su-Xia Sun,

    1. Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, China
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    • The authors contributed equally to this work.

  • Xian-Chao Cheng,

    1. Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, China
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  • Shu-Qing Wang,

    1. Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, China
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  • Wei-Li Dong,

    1. Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, China
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  • Run-Ling Wang,

    Corresponding author
    1. Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, China
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  • Wei-Ren Xu

    1. Tianjin Institute of Pharmaceutical Research (TIPR), Tianjin, China
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Abstract

Owing to its special role as a negative regulator in both insulin and leptin signaling, protein tyrosine phosphatase-1B (PTP1B) has drawn considerable attention as a target for treating type 2 diabetes and obesity. It, however, is a great challenge to discover inhibitors specific to each PTP due to the highly homologous. In this study, a series of compounds were discovered to inhibit PTP1B based on imidazolidine-2,4-dione by means of ‘core hopping’. A selective PTP1B inhibitor (comp#h) was identified, and molecular dynamics simulation and binding free energy calculation were carried out to propose the most likely binding mode of comp#h with PTP1B. The findings reported here may provide a new strategy in discovering selective and effective inhibitors for treating diabetes.

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