Screening And Study Of Multi-target Inhibitors For Non-small Cell Lung Cancer

In recent years,the rapid development of targeted drug therapy has effectively improved the survival and quality of life of cancer patients,especially non-small cell lung cancer patients,but the current research and development of kinase inhibitors is still in the initial stage,and only drugs targeting a few kinase targets have been approved and marketed,and they have the disadvantages of being prone to drug resistance and insufficient efficacy.Recent studies have found that dual targeting of ALK and MEK can reduce or even eliminate the resistance of ALK inhibitors caused by the activation of MAPK pathway;dual targeting of NUAK1 and ULK1 can synergistically induce cancer cell apoptosis.On the basis of summarizing the treatment methods and research status of nonsmall cell lung cancer,this study analyzed the mechanism of action and binding modes of existing inhibitors,and screened ALK/MEK and NUAK1/ULK1 dual-target inhibitors by computer-aided drug design method.The main research contents are as follows:1.The ALK and MEK pharmacophore models were constructed using the crystal structures of ALK-ligand and MEK-ligand complexes,and their classification capabilities were verified.Through the ALK and MEK pharmacophore models,the ZINC 10 M compound database was screened in turn.Then,the positive reference compounds were used as the screening standards for molecular docking screening,and the ADMET properties of the compounds were predicted.Compound AM1 with excellent druggability,safety and docking performance was selected,and the molecular dynamics simulation was used to verify its affinity on the two targets.After analyzing the binding mode of AM1 with ALK and MEK,AM2 and AM3 with good druggability and ADMET properties were obtained by structural modification of AM1.Compound AM2 has a lower binding free energy than the reference compound,and is expected to be an ALK/MEK dual-target inhibitor that can prevent drug resistance.2.The pharmacophore models were established and evaluated by the crystal structures of the ULK1-inhibitor complexes,and the ZINC 2M compound database was virtually screened using a ULK1 pharmacophore.The structure of NUAK1 was constructed by homology modeling and the binding site of its inhibitors was identified,and the molecular library was screened by dual-target molecular docking.Then,a clinical toxicity prediction model was trained using the Deep Chem deep learning platform and compound toxicity screening was performed,and 3 potential inhibitors were obtained.Finally,molecular dynamics simulations and PBSA binding free energy calculations were performed,and a false positive compound with unstable binding was exclude.Compounds NU1 and NU3 have better affinity than the two reference compounds,and they are potential dual-target inhibitors of NUAK1/ULK1.In summary,this study is based on the theoretical basis of the synergistic effect of ALK and MEK,NUAK1 and ULK1,and ALK/MEK and NUAK1/ULK1 dual-target hit compounds were obtained through virtual screening of large molecular databases and molecular structure modification.It is expected to solve the problems that ALK inhibitors are prone to drug resistance and the anti-cancer effect of NUAK1 inhibitors is insufficient.This study will greatly advance the discovery process of lead compounds and provide new molecular design ideas for the development of new drugs for non-small cell lung cancer.