Novel Dual-Site-Binding Neuraminidase Inhibitor from Virtual Screening by Pharmacophore and Molecular Dynamics Methods

Authors

  • Kun Huang,

    1. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, Jiangsu 210009, China
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  • Xiaowen Wu,

    1. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, Jiangsu 210009, China
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  • Zhengyu Jiang,

    1. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, Jiangsu 210009, China
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  • Haopeng Sun,

    Corresponding author
    1. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, Jiangsu 210009, China
    2. State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, Jiangsu 210009, China
    • Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, Jiangsu 210009, China
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  • Qidong You

    Corresponding author
    1. Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 210009, China
    2. State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, Jiangsu 210009, China
    • Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 210009, China, Tel.: 0086-025-83271351; Fax: 0086-025-83271351
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Abstract

Neuraminidase is a significant anti-influenza target that plays crucial role in virus replication cycle. The discovery of 150-cavity in Group-1 neuraminidase provides us a novel mentality of designing inhibitor which can bind with both conserved site and 150-cavity. In order to discover novel dual-site-binding inhibitors, a 3D chemical-feature-based pharmacophore model was established to cover dual-site in neuraminidase. The dual-site-binding model was consistent in predicting the binding conformation of Group-1 neuraminidase inhibitor and applied for virtual screening of Specs database. Compound 4 (ZINC05790048) that aligned well to the model was selected after multiple filtrations for molecular dynamics simulations, indicating improved binding energy with neuraminidase. It can sever as the lead compound for a novel series of inhibitors.

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