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

Yilin Hou, Yuanyuan Zhao and Yu Li
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Yilin Hou: 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
Yu Li: College of Environmental Science and Engineering, North China Electric Power University, Beijing 102206, China

IJERPH, 2020, vol. 17, issue 18, 1-18

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%).

Keywords: fluoroquinolone; plasma protein binding rate; three-dimensional quantitative structure–activity relationship; molecular modification; molecular docking; molecular dynamics simulation (search for similar items in EconPapers)
JEL-codes: I I1 I3 Q Q5 (search for similar items in EconPapers)
Date: 2020
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (2)

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