3D-QSAR And Molecular Docking Studies Of Epigenetic Factor EZH2/EZH1

Malignant tumors are a serious threat to human health.With the development of society and environmental changes tumor incidence has increased year by year trend.More and more studies have shown that epigenetic regulation plays a vital role in the development and progression of tumors.Epigenetic factor EZH2 protein as a potential anti-tumor target,has been observed in a variety of tumor cells in the phenomenon of overexpression.In recent years,studies have also found that EZH1 as EZH2 homologous protein in its damage or deletion as a key reserve enzyme can compensate for EZH2 is not present function.In order to inhibit the related function of EZH2 protein and its overexpression,the activity of EZH2 and EZHI was controlled at the same time.In this study,3D-QSA R studies of EZH2 and EZH1 were carried out by constructing compound library,and the binding mode between EZH2 and EZH1 was compared by homologous modeling and molecular docking.Our study provides a useful information for the discovery of novel EZH2/EZHI selective inhibitors.This dissertation is composed of four chaptersChapter 1:A brief overview of epigenetic and computer-aided drug discovery which focuses on the pharmacophore model,3D-QSAR and molecular docking.Chapter 2:The relationship between structure and activity of EZH2 inhibitors were studied using Comparative molecular field analysis and Comparative molecular similarity indices analysis methods.A high reliability and strong predictive QSAR model was obtained.Also,the main structural factors affecting the biological activity were obtained,and were used for structural modification.Chapter 3:The relationship between structure and activity of EZH1 inhibitors were studied using 3D-QSAR methods.A high reliability and strong predictive QSAR model was obtained.It can be used as the supplement the drug design of EZH1 inhibitors.Chapter 4:The three-dimensional structure of EZH1 was constructed by homology modeling,and the binding sites of EZH2 inhibitors and EZH1 inhibitors in protein were analyzed by molecular docking method.Combining molecular docking and 3D-QSAR to predict compounds.