3D-QSAR,Molecular Docking And Molecular Dynamics Studies Of HIV-1 Integrase Chain Transfer Inhibitors

Objective:Human immunodeficiency virus(HIV)is a retrovirus that infects cells in the immune system,destroying or damaging its ftunction and over time resulting in acquired immunodeficiency syndrome(AIDS).HIV integrase is an important target for the treatment of AIDS.The current clinical treatment of this disease is the first generation of integrase strand transfer inhibitors including raltegravir(RAL),elvitegravir(EVG)and the second generation inhibitor of dolotegravir(DTG).Although current drug treatment regimens are very effective,there are still long-term toxicity issues.The development and tolerance of cross-resistance and mechanism types are poor,so it is necessary to find new drugs that are active against viruses and safer for long-term use.Computational chemistry has evolved into an important contributor to rational drug design.Quantitative structure-activity relationship(QSAR)leads to a quantitative correlation between chemical structure and biological activity.This article starts with intrinsic strand transfer inhibitors of naphthyridines and indoles,we used molecular dynamics simulation to study the mechanism of action of two classes of heterocycle molecules and integrase strand transfer and the selective mechanism of active small molecules on integrase respectively,thus providing a new idea for rational design of integrase strand transfer inhibitors.The comparative molecular field analysis(CoMFA)and comparative molecular similarity indices analysis(CoMSIA)were used to construct three-dimensional quantitative structure-activity relationships models.The relationship between compound structures and activities were obtained by analyzing established models to guide the structural optimization of compounds on this basis.Method:In this thesis,the molecular docking and molecular dynamics simulation methods were firstly used to explore the binding mode and interaction mechanism of the compound and the target protein.Then the three-dimensional quantitative structure-activity relationship method was used to construct the CoMFA and CoMSIA models,and the structure of the compound was obtained by analyzing the model.Relationship with activity.Result:Through the establishment of reliable and stable CoMFA and CoMSIA models,we obtained the key structures affecting the biological activity of these compounds.By analyzing the equipotential map of the CoMFA model,we obtained the effect of introducing groups of different sizes on the activity of the compounds,and analyzed CoMSIA.The equipotential map of the model,we obtained the effect of hydrophobic interaction and hydrogen bonding interaction on the activity of the compound.The binding mode and binding pocket of the compound to the protein were obtained by molecular docking,and the key amino acids which maintain the stability of the binding of the compound to the INSTIs protein were obtained,and the importance of interaction between hydrophobic interaction and hydrogen bonding was further explained.Finally,further verification by molecular dynamics simulation was carried out.The docking results provide us with a new compound to design later.This article is divided into five chapters:In the first chapter of the thesis,we mainly describes the pathogenesis and etiology of HIV,the structure,active site and catalytic mechanism of HIV integrase,and the research situation of integrase strand transfer inhibitors.On this basis,we also systematically expounded the research progress of the inhibitory activities of naphthyridines and indoles.In the second chapter of the paper,we outlines the computational chemistry methods used in this study,including molecular docking,molecular dynamics(MD)simulation,and the construction of three-dimensional quantitative structure-activity relationship models.In the third chapter,64 naphthyridines as strand transfer inhibitors were studied by molecular docking methods.The interaction binding mode and mechanism of action between naphthyridines and the target enzyme were discussed,and molecular docking was further verified by molecular dynamics simulation.The result for molecular dynamics(MD)simulation and binding free energy calculations show that the amino acid residues Asp 128 and Glu221 form hydrogen bonding interactions with the oxygen atom of the carbonyl group on the parent nucleus of the naphthyridines respectively,the oxygen atom of the 6-substituted ester group on the nucleus forms a hydrogen bond interaction with the amino acid residues Tyr212 and Glnl 86,respectively.In the fourth chapter,the three-dimensional quantitative structure-activity relationship of 64 naphthyridines was studied by using CoMFA and CoMSIA.A stable and robust CoMFA and CoMSIA models were established,and three-dimensional contour maps generated from these models were used to explain the relationship between the compounds and the inhibitory activity.We wish to provide useful information for designing strand transfer inhibitors with high antiviral activity and low in vivo toxicity.In the fifth chapter,molecular docking and molecular dynamics(MD)simulation were used to study 25 of indoles as strand transfer inhibitors and explore the mechanism of action between this class of compounds and the target protein.The key amino acids affecting the stability of ligand-receptor binding were obtained.Finally,the study was summarized and prospected.