Highly biodegradable fluoroquinolone derivatives designed using the 3D-QSAR model and biodegradation pathways analysis

A three-dimensional quantitative structure-activity relationship (3D-QSAR) model was established based on molecular structures and docking scores (representing the biodegradability); the scores were obtained for 23 fluoroquinolones (FQs) and the oxidoreductase (PDB ID: 1YZP) of Phanerochaete chrysosporium in the aerobic process of municipal wastewater treatment plants. In the Comparative Molecular Field Analysis (CoMFA) model, q(2) was 0.516 and r(pred)(2), a was 0.727, which showed that the model was reliable and robust. The modification information obtained by the contour maps showed that introducing electronegative, bulky or electropositive groups at different active sites could increase the biodegradability of fluoroquinolone derivatives. Using levofloxacin (LEV) as a modified molecule, 35 fluoroquinolone derivatives with higher biodegradability than LEV were designed. After the evaluation of genotoxicity, bioconcentration and photodegradation, Derivative-15, with higher biodegradability (increased by 27.85%), higher genotoxicity, higher photodegradation and lower bioconcentration, was identified as the most environmentally friendly fluoroquinolone derivative. The 2D-QSAR model of FQ biodegradability was established through the quantization parameters, and q(+) was identified as the main parameter affecting the biodegradability of FQs through sensitivity analysis. In addition, the docking results of LEV and Derivative-15 with the oxidoreductase in P. chrysosporium showed that the electrostatic field force between Derivative-15 and the amino acid residues promoted the binding of the donor to the receptor protein, thereby increasing the biodegradability of Derivative-15. Additionally, molecular dynamics simulations revealed that the enhancement of the electrostatic field force with Derivative-15 could promote the binding of the ligand to the receptor, which was basically consistent with the conclusion of molecular docking. Finally, the three microbial degradation pathways of LEV and Derivative-15 were also proposed. The total energy barrier value of the pathway with the lowest total energy barrier of biodegradation was reduced by 32.07%, which was basically consistent with the enhancement of biodegradability of Derivative-15.