Prediction Of Dioxin Toxicity And Theoretical Calculation Of Toxicology

With the rapid development of economy,environmental pollution has become prominent.Persistent organic pollutants have the characteristics of high toxicity,persistence and bioaccumulation,which have attracted more and more attention.As a kind of persistent organic pollutants,dioxins have a large number of homologues,some of which are extremely toxic.However,the toxicity experiments of dioxins are time-consuming and laborious,which results in a serious lack of toxicity data.The lack of toxicity data and the unclear toxicity mechanism have a greatly impact on human production and daily life.This paper aims to explore and predict the toxicity of dioxin efficiently and accurately using the theoretical calculation methods of chemoinformatics,speculate on its toxicology,which makes up for the shortcomings of experimental chemistry.Chapter 1 Review of persistent organic pollutants dioxins and chemoinformatics.In chapter 1,we summarized the related background of dioxin and the conclusion by previous researchers in the study of dioxin;we introduced the related knowledge of chemoinformatics and the chemoinformatics methods used in this paper.Chapter 2 In silico toxicity evaluation of dioxins using structure-activity relationship?SAR?and two-dimensional quantitative structure-activity relationship?2D-QSAR?.In chapter 2,our main purpose is to use qualitative structural-activity relationship analysis and two-dimensional quantitative structure-activity methods to explore the factors that affect the toxicity of dioxins and predict the toxicity data of dioxins.Firstly,the qualitative structure-activity relationship was used to analyze the relationship between the structures of 60 dioxins and corresponding pEC₅₀ values.It was concluded that the factors affecting the toxicity of dioxins were mainly related to the types of substituents and the positions of substitutions.In order to verify the above analysis,two-dimensional quantitative structure-activity relationships were used to establish linear and non-linear 2D-QSAR models.Both the linear model and the non-linear model have good fitness ability,reliability,robustness and predicative ability after verification.These two established models were used to predict pEC₅₀values of 162 dioxin lacking toxicity data,and the accuracy of predictions was evaluated using the method proposed by Roy.The results show that the predicted values obtained from the two models have high reliability.In addition,the two-dimensional quantitative structure-activity relationship also revealed five structural factors affecting toxicity.The toxicity mechanism revealed by these five structural factors confirms the speculative conclusions obtained from the qualitative structure-activity relationship analysis.This work supplemented the toxicity database of dioxins and provided a preliminary basis for further research on the toxicity mechanism of dioxins.Chapter 3 Research on dioxin toxicity and binding mode with AhR based on three-dimensional quantitative structure-activity relationship?3D-QSAR?and molecular docking.In chapter 3,our main purpose is to explore the quantitative relationship between the three-dimensional structure of dioxins and toxicity data accurately,and determine the binding mode of dioxin molecules to receptor?AhR?.Firstly,CoMFA and CoMSIA were used to establish 3D-QSAR models of two kinds of dioxins with different skeletons.Through the analysis of the contour maps,several fields affecting dioxins toxicity were found,and the corresponding structural factors that affect molecular toxicity were determined.In order to observe the binding mode between ligands and protein receptors intuitively,molecular docking was used to study the interaction between several typical dioxins molecules and AhR.The results indicated different binding modes between different molecules and receptor,which explains the difference in toxicity of small ligands.The conclusions obtained from this work further validated the conclusions obtained in the previous work,and together revealed the structural factors affecting the molecular toxicity of dioxins,providing a basis for further research on the toxicology of dioxins.Chapter 4 Main conclusions and prospects.In Chapter 4,all the work of this paper was summarized and all the important conclusions from this paper were listed.