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

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 (logfb) as the dependent variable to predict the logfb 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 logfb 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%).

SUBMITTER: Hou Y

PROVIDER: S-EPMC7560044 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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

Hou Yilin Y Zhao Yuanyuan Y Li Yu Y

International journal of environmental research and public health 20200911 18

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 (logfb) as the dependent variable to predict the logfb values of remaining quinolones in this study. In addition, the mono-substituted and bis-substituted reaction schemes that significantly influenced ...[more]

PMID: 32932916

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Project description:The aurora kinase is a key enzyme that is implicated in tumor growth. Research revealed that small molecules that target aurora kinase have beneficial effects as anticancer agents. In the present study, in order to identify potential antibreast cancer agents with aurora kinase inhibitory activity, we employed QSARINS software to perform the quantitative structure-activity relationship (QSAR). The statistical values resulted from the study include R2 = 0.8902, CCCtr = 0.7580, Q2 LOO = 0.7875, Q2LMO = 0.7624, CCCcv = 0.7535, R2ext = 0.8735, and CCCext = 0.8783. Among the four generated models, the two best models encompass five important variables, including PSA, EstateVSA5, MoRSEP3, MATSp5, and RDFC24. The parameters including the atomic volume, atomic charges, and Sanderson's electronegativity played an important role in designing newer lead compounds. Based on the above data, we have designed six series of compounds including 1a-e, 2a-e, 3a-e, 4a-e, 5a-e, and 6a-e. All these compounds were subjected to molecular docking studies by using AutoDock v4.2.6 against the aurora kinase protein (1MQ4). Among the above 30 compounds, the 2-amino thiazole derivatives 1a, 2a, 3e, 4d, 5d, and 6d have excellent binding interactions with the active site of 1MQ4. Compound 1a had the highest docking score (-9.67) and hence was additionally subjected to molecular dynamic simulation investigations for 100 ns. The stable binding of compound 1a with 1MQ4 was verified by RMSD, RMSF, RoG, H-bond, molecular mechanics-generalized Born surface area (MM-GBSA), free binding energy calculations, and solvent-accessible surface area (SASA) analyses. Furthermore, newly designed compound 1a exhibited excellent ADMET properties. Based on the above findings, we propose that the designed compound 1a may be utilized as the best theoretical lead for future experimental research of selective inhibition of aurora kinase, therefore assisting in the creation of new antibreast cancer drugs.

Dataset Information

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

Publications

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

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