Design Of SGK1/Src Dual Target Inhibitor And Exploration Of Synthetic Route

In recent years,the development trend of anti-tumor drugs has begun to change,from the initial research of cytotoxic drugs to the research of molecular implants.The emergence of molecular alternative drugs has made the treatment of cancer more targeted.Dual-targeted drugs have gradually become the mainstream.Compared with single-target drugs,dual-target drugs have stronger therapeutic effects,fewer side effects,and greatly reduce the probability of drug resistance.Therefore,the research and development of dual-target drugs is of great significance.In this study,SGK1/Src dual inhibitors were designed by computer-aided drug design.Firstly,through the pharmacophore model and molecular docking,seven million molecules were screened.Then,6 compounds were obtained.The results of molecular dynamics simulation of compound 1 showed that it has good binding stability to both receptors.According to the binding site of compound 1 with two receptors,corresponding modifications were made,and 6 novel designed compounds were obtained.The docking scores of novel designed compounds were lower than that of compound 1.Finally,synthesize the designed compound and determine its anti-tumor activity in order to find a lead compound that has a significant inhibitory effect on the SGK1/Src dual target.The main contents are as follows:1.The method based on ligand-receptor complex was used to construct the pharmacophore models of SGK1 and Src,respectively.In order to obtain compounds that can meet the two pharmacophore models at the same time,using the established pharmacophore model as the screening standard to screened the small molecule compound library.2.The method of molecular docking was used to conduct a secondary screening of the selected compounds,the compounds with low scores for the docking of the two targets were determined their ADMET properties.3.The selected compound 1-((5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)methyl)-3-(2-methoxy-4-methyl Phenyl)urea was subjected to 40 ns molecular dynamics simulation to detect its binding mode to the SGK1 and Src receptors,and the compound structure was modified according to the ligand-receptor binding.4.The urea group-linked benzene ring and triazole derivatives were synthesized.