| In the drug treatment of non-small cell lung cancer,targeted therapy drugs can accurately act on the tumor tissue,reduce the damage to the surrounding normal tissues and side effects.In this thesis,based on molecular docking and molecular dynamics simulation,the molecular mechanism of HAPs-HBV,the mechanism of Brigatinib on wild type and its mutant ALK and the determinants of the selectivity of ALK kinase inhibitors were studied.Next,the differential gene expression and protein interactions in non-small cell lung cancer were explored.Chapter 1: The brief description on the study of HBV and NSCLC.In addition,the molecular simulation methods and bioinformatics were briefly introduced.Chapter 2: The non-nucleoside drugs have been developed to treat HBV infection owing to their increased efficacy and lesser side effects,in which heteroaryldihydropyrimidines(HAPs)have been identified as effective inhibitors of HBV capsid.In this paper,the binding mechanism of HAPs targeting on HBV capsid protein was explored.The obtained models of comparative molecular field analysis and comparative molecular similarity indices analysis enable the sufficient interpretation of structure-activity relationship of HAPs-HBV.The binding free energy analysis correlates with the experimental data.The computational results disclose that the non-polar contribution is the major driving force and Y132 A mutation enhances the binding affinity for inhibitor 2 bound to HBV.The hydrogen bond interactions between the inhibitors and Trp102 help to stabilize the conformation of HAPs-HBV.The study provides insight into the binding mechanism of HAPs-HBV and would be useful for the rational design and modification of new lead compounds of HAP drugs.Chapter 3: As a potent and selective drug,brigatinib exhibits high efficacy against wild-type and mutant Anaplastic Lymphoma Kinase(ALK)proteins to treat non-small cell lung cancer.The aim is to investigate the mechanisms of brigatinib binding to wild type and its mutated ALKs.Comparison between brigatinib and crizotinib suggested that brigatinib was anchored by only two hydrogen bonds with the residue Met1199 of hinge region and was more sensitivity to ALK,especially the residues Lys1150 had the strong electrostatic interactions with the dimethylphosphine oxide moiety in brigatinib which did not render hydrogen bonds form on account of strong polar interaction.These mutations all influenced mainly the flexibility of P-loop region and DFG sequences in varying degrees compared to WT ALK-brigatinib,but did not impair the hydrogen bonds between brigatinib and Met1199,but induced diverse conformational changes lead to the binding potency of ALK-brigatinib and the obvious energy variation of Asp1270.Together,several guidelines were provided for the development of more effective ALK inhibitors.Chapter 4: As an attractive therapeutic target for non-small-cell lung cancer(NSCLC),Anaplastic lymphoma kinase(ALK)has got increased attention.Recently,2,4-Diarylaminopyrimidines with high inhibitory activity over InsR/IGF1 R were reported as ALK inhibitors,which harboring phosphine oxide moiety.The selectivity of ALK inhibitors is an enormous challenge.In this work,it is the first time to reveal that the incorporation of dimethylphosphine oxide moiety and the smaller active pocket of ALK is key factor in the selectivity of inhibitor 11 q towards ALK over IGF1R/InsR.Comparison with inhibitors-ALK structure reveals subtle changes in the binding pocket,suggesting that these small changes are mainly associated with the flexibility of P-loop and residues K1150 and D1270.The replacement of the dimethylphosphine oxide and methylpiperazine of inhibitor 11 q would alter the major inhibitory effects of binding and activation.The results further combined 3D-QSAR can not only profile the binding mechanism between the 2,4-Diarylaminopyrimidines inhibitors and ALK,but also supply the useful information for the rational design of a more potential small molecule inhibitor bound to ALK receptor.Chapter 5: Exploring the function of differentially expressed genes in non-small cell lung cancer,and the interaction between its associated encoded proteins,and then analyzing important closely genes of non-small cell lung cancer is a important issue.By parsing the GSE19408 chip data,a total of 895 differentially expressed genes were obtained,of which 299 were up-regulated genes and 596 were down-regulated genes.These genes mainly occur in the process of protein metabolism,proteolysis,mitosis and cell division.Furthermore,TOP2 A,CCNB1,CCNA2,CDK1 and TTK may be the key target genes of NSCLC through the protein interactions network.At the molecular level,it provides insights to the NSCLC development mechanism. |
