Design Of Multiple Inhibitory Compounds Of Sphingosine Kinase 1

The high incidence of cancer causes millions of deaths worldwide every year,so the discovery of effective drugs to treat cancer is the focus of the pharmaceutical industry.Cancer treatment has gone through three stages,radiotherapy and chemotherapy,targeted therapy and immunotherapy.Targeted therapy interferes with the growth,division and diffusion of cancer cells by acting on key targets by drugs to achieve the purpose of treatment.Compared with single-target drugs,multi-target drugs have stronger therapeutic effects,lower toxic and side effects,and can overcome the problems of non-response and drug resistance of single-target inhibitors.In recent years,studies have found that sphingosine kinase 1 is involved in the conversion of intracellular sphingosine to sphingosine-1-phosphate.Sphingosine-1-phosphate not only affects the growth,proliferation,differentiation,migration,apoptosis and angiogenesis of cancer cells,but also regulates the tumor immune microenvironment.The combination of sphingosine kinase 1 inhibitor and sirtuin 1inhibitor can overcome the resistance of tyrosine kinase inhibitor in the treatment of leukemia.Therefore,the identification of dual-target inhibitors of sphingosine kinase 1and sirtuin 1 is of great significance for the design of drugs for the treatment of leukemia.In addition,the combination of sphingosine kinase 1 inhibitor and programmed death receptor 1 inhibitor can significantly reduce melanoma and prolong survival.The combination of sphingosine kinase 1 inhibitor and programmed death receptor 1inhibitor not only inhibits the growth of tumor cells,reduces the expression of programmed death receptor 1 ligand 1,but also blocks the binding of programmed death receptor 1 to programmed death receptor 1 ligand 1.Therefore,based on the synergistic effect of sphingosine kinase 1 and sirtuin 1 or programmed death receptor 1,it plays an important role in the discovery of dual-target inhibitors for the treatment of leukemia and cancer.In this study,sphingosine kinase 1 with sirtuin 1 or programmed death receptor 1were designed as a dual-target inhibitors to obtain two different series of dual-target inhibitors.This work mainly uses computer-aided drug design methods to perform virtual screening,pharmacokinetic property prediction,molecular dynamics simulation and relative binding free energy calculation on different databases,and then modifies the obtained molecular skeleton,and predicts the inhibitory possibility of candidate compounds on different cells through online websites.The virtual screening methods include pharmacophore model screening,high-throughput screening and molecular docking.In addition,the synthetic route of the target compound was studied and explored.The main contents of this work are as follows:1.7.5 million small molecules were obtained from the ZINC database,and the pharmacophore models of sphingosine kinase 1 and sirtuin 1 were generated by Schr?dinger 2019.6 for preliminary screening.The pharmacokinetic properties of the selected small molecules were predicted by Discovery Studio 2016 Client,and obtained small molecules that meet the standards.After that,Schr?dinger 2019.6 performed molecular docking screening of small molecules with sphingosine kinase 1 and sirtuin1,and used GROMACS 5.1.2 to perform 100 ns molecular dynamics simulation of the docking dominant conformation.The binding free energy between the protein-ligand complex was calculated to screen the lead compound 1-3(ZINC000011957607).The structure of lead compounds 1-3 was modified,and the reasonable structure was evaluated by molecular docking.The pharmacokinetic properties of the candidate compounds were predicted by the Swiss ADME website,and the probability of inhibition of leukemia cells was predicted by PASS online.Then,the synthetic route of target compound 1-3 was proposed and explored.2.Discovery Studio 2016 Client predicted the pharmacokinetic properties of407,270 natural products in the COCONUT database,and Schr?dinger 2019.6 predicted the drug-like pocket of programmed death receptor 1.After that,the natural products were subjected to high-throughput screening,molecular docking,MM/GBSA calculation with sphingosine kinase 1 and programmed death receptor 1,and 100 ns molecular dynamics simulation was performed on the dominant conformation of the protein-complex.The molecular dynamics simulation trajectory was analyzed,and the protein-complex binding free energy during the simulation was calculated to screen out natural products 2-2.Therefore,natural product 2-2 was used as the molecular skeleton for modification,and the modified structure was evaluated by molecular docking.Then,the pharmacokinetic properties and the probability of cancer cell inhibitory activity of all candidate compounds were predicted on the Swiss ADME and PASS online websites.