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Environmentally Friendly Fluoroquinolone Derivatives with Lower Plasma Protein Binding Rate Designed Using 3D-QSAR, Molecular Docking and Molecular Dynamics Simulation

Author

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  • Yilin Hou

    (College of Environmental Science and Engineering, North China Electric Power University, Beijing 102206, China
    MOE Key Laboratory of Resources and Environmental System Optimization, College of Environmental Science and Engineering, North China Electric Power University, Beijing 102206, China)

  • Yuanyuan Zhao

    (College of Environmental Science and Engineering, North China Electric Power University, Beijing 102206, China
    MOE Key Laboratory of Resources and Environmental System Optimization, College of Environmental Science and Engineering, North China Electric Power University, Beijing 102206, China)

  • Yu Li

    (College of Environmental Science and Engineering, North China Electric Power University, Beijing 102206, China
    MOE Key Laboratory of Resources and Environmental System Optimization, College of Environmental Science and Engineering, North China Electric Power University, Beijing 102206, China)

Abstract

Comparative molecular similarity index analysis (CoMSIA) was used to establish a three-dimensional quantitative structure–activity relationship (3D-QSAR) model with structural parameters of quinolones as the independent variables and plasma protein binding rate (log f b ) as the dependent variable to predict the log f b values of remaining quinolones in this study. In addition, the mono-substituted and bis-substituted reaction schemes that significantly influenced the plasma protein binding rate of quinolones were determined through an analysis of the 3D-QSAR contour maps. It was found that the replacement of small groups, hydrophobic groups, electronegative groups, or hydrogen bond acceptor groups at the substitution sites significantly reduce the log f b values of quinolone derivatives. Furthermore, the mechanism of decrease in binding rate between trovafloxacin (TRO) derivatives and plasma protein was revealed qualitatively and quantitatively based on molecular docking and molecular dynamics simulation. After modification of the target molecule, 11 TRO derivatives with low plasma protein binding rates were screened (reduced by 0.50–24.18%). Compared with the target molecule, the molecular genotoxicity and photodegradability of the TRO derivatives was higher (genotoxicity increased by 4.89–21.36%, and photodegradability increased by 9.04–20.56%), and their bioconcentration was significantly lower (by 36.90–61.41%).

Suggested Citation

  • Yilin Hou & Yuanyuan Zhao & Yu Li, 2020. "Environmentally Friendly Fluoroquinolone Derivatives with Lower Plasma Protein Binding Rate Designed Using 3D-QSAR, Molecular Docking and Molecular Dynamics Simulation," IJERPH, MDPI, vol. 17(18), pages 1-18, September.
    • Handle: RePEc:gam:jijerp:v:17:y:2020:i:18:p:6626-:d:412219
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    References listed on IDEAS

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    1. Lu-ze Yang & Miao Liu, 2020. "A Double-Activity (Green Algae Toxicity and Bacterial Genotoxicity) 3D-QSAR Model Based on the Comprehensive Index Method and Its Application in Fluoroquinolones’ Modification," IJERPH, MDPI, vol. 17(3), pages 1-14, February.
    2. Zhixing Ren & Yingwei Wang & Haihong Xu & Yufei Li & Song Han, 2019. "Fuzzy Comprehensive Evaluation Assistant 3D-QSAR of Environmentally Friendly FQs to Reduce ADRs," IJERPH, MDPI, vol. 16(17), pages 1-20, August.
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    Cited by:

    1. Peixuan Sun & Yuanyuan Zhao & Luze Yang & Zhixing Ren & Wenjin Zhao, 2020. "Environmentally Friendly Quinolones Design for a Two-Way Choice between Biotoxicity and Genotoxicity through Double-Activity 3D-QSAR Model Coupled with the Variation Weighting Method," IJERPH, MDPI, vol. 17(24), pages 1-22, December.
    2. Peixuan Sun & Wenjin Zhao, 2021. "Strategies to Control Human Health Risks Arising from Antibiotics in the Environment: Molecular Modification of QNs for Enhanced Plant–Microbial Synergistic Degradation," IJERPH, MDPI, vol. 18(20), pages 1-26, October.

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