Application Of QSAR Method In Evaluation Of Inhibitor Activity Effect

In this paper,the quantitative activity-activity-related(QSAR)method was used to evaluate the biological activity of African trypanosomiasis(HAT)inhibitor and epoxide hydrolase(hsEH)inhibitor,and the mechanism of interaction between ligand and protein was studied by the molecular docking and molecular dynamics simulation.The results show that the established QSAR model can accurately predict the relative biological activity of similar inhibitors.Molecular docking and molecular dynamics studies were conducted to analyze the interaction between the inhibitor and the target protein.Provide guidance for the prediction and design of new inhibitors.(1)2D-QSAR models are developed to predict the activity against Trypanosoma brucei rhodesiense of amide and urea derivatives of thiazol-2-ethylamines.The VSMVI(variable selection method based on variable interaction)technique is used to select optimal subset from large-size molecular descriptors.Multiple linear regression(MLR)method is employed to construct the QSAR models.The correlation coefficient of leave-one-out cross validation(q~2=0.8574)and fitting correlation coefficient of models(r~2=0.8892)show that the model is robust and has good fitting and prediction for selecting bioactivities.The descriptor of the2D-QSAR model reflects,to some extent,that the two-dimensional structure and hydrophobicity of the molecules play an important role on the inhibitory activity.Simultaneously,the models of three-dimensional quantitative structure-activity relationship(3D-QSAR)based on CoMFA and CoMSIA show a significant correlation and strong predictive ability(CoMFA:r~2=0.924,q~2=0.516.CoMSIA:r~2=0.944,q~2=0.531).The highest contribution rate of CoMSIA hydrophobic field indicates that the hydrophobic interaction of molecules has an important effect on the inhibitory activity.(2)The interaction mode and characteristics of the new amide-phosphonate derivatives on human soluble epoxide hydrolase(hsEH)were studied by quantitative structure-activity relationship(QSAR),molecular docking and molecular dynamics simulation(MD).The2D-QSAR model shows the high fitting ability and high predictive ability(r~2=0.942,q~2=0.918).And the model shows that the the number of C-N bonds of the amide-phosphonate derivatives are important factors to the inhibit hsEH activity.The 3D-QSAR model of comparative molecular field analysis(CoMFA)and comparative molecular similarity index analysis(CoMSIA)show a significant correlation and strong ability of prediction(CoMFA:r~2=0.986,q~2=0.619;CoMSIA:r~2=0.912,q~2=0.630).And indicate that the hydrophobic interaction,electrostatic force and hydrogen bond play important roles for the activity inhibitory of hsEH.The molecular docking results indicate that the intramolecular amide groups,phosphonate groups and the-NH-molecular structure can form stable hydrogen bonds with the amino acid residues HIS524,ASP335,TYR383,TYR466,GLN384,Trp525 to increase the stability of binding,and the hydrogen bond,strong hydrophobic forces at the binding sites of hydrophobic residues,and the?-?stacking also play important roles.The reliability of the docking results of the binding sites was verified by the molecular dynamics simulation,and the rationality of the docking mechanism was verified by the free energy.