Study On The Interactions Between HIV-1 Integrase With Inhibitors And Viral DNA With Molecular Simulation Approaches

From 1990s, with the development of theoretical and computational methods as well as molecular modeling technology, drug design came into a brand-new era, which mainly involves the rational drug design. The core of the contents of rational drug design is discovery of the new selective drugs against certain targets such as enzyme, receptor, ion channel and nucleic acid, based on some endogenous ligands or characteristic of the chemical structures of some natural products. The kernel of the methodology focus on the studies of the interactions between receptor and ligand. Rational drug design has become an active research area. In this dissertation, molecular docking, molecular dynamics simulation and binding free energy calculation were used to study the binding modes, binding affinity and drug resistance of HIV-1 integrase and its inhibitors. The possible DNA binding sites were also investigated. These studies will be helpful for design and discovery of new active anti-AIDS drugs. The dissertation mainly includes the following three aspects: study on interactions between HIV-1 integrase and its dicaffeoyl inhibitors through molecular modeling approach; investigations on HIV-1 integrase/DNA binding interactions with the molecular docking approach; study on the HIV-1 integrase drug resistance to the clinical trial drug S-1360. X-ray and NMR experiments have revealed the structures of the three domains on HIV-1 integrase, which is important for structure-based drug design. The binding mode of a series of dicaffeoyl-or digalloyl pyrroliding and furan derivatives inhibitors with HIV-1 integrase was proposed by using molecular docking and molecular dynamics simulation methods. The results indicate that the interactions between HIV-1 integrase conserved DDE motif and caffeoyl -or galloyl group of inhibitors play a critical role in the inhibition of integrase activity. The binding affinity between integrase and inhibitors was improved when the side chain groups were galloyls. The linear interaction energy method was used to calculate the binding free energies of HIV-1 integrase and their inhibitors. The predicted values are in good agreement with the experimental data, with a root mean square deviation (RMSD) of 1.39 kJ/mol. The above results provide us useful information for structure-based HIV-1 integrase inhibitor design. HIV-1 integrase (IN) is a key enzyme in the process of HIV-1 replication and can catalyse the insertion of the viral cDNA into host chromosomes. The knowledge of the binding sites between integrase tetramer and viral DNA at atomic level will be very helpful for understanding integrase catalytic mechanism and discovery of inhibitors. Until now, the binding sites and binding modes between HIV-1 IN and viral DNA have not been clarified. In this work, the full length HIV-1 integrase tetramer was obtained by homology modeling. Molecular docking method was used to explore the binding site of integrase with 27bp DNA. The docking results show that the binding sites locate in the saddle-shaped groove produced by two monomers of C-term and N-term domains for each of the IN dimer. In addition, DNA may interact integrase tetramer by contacting with both the C-term and N-term domains from one dimer and the core domain from the other dimer. The 3'end processed DNA and intact DNA interact with integrase in the similar way. The results have good agreement with the known experimental data obtained from the photo-cross-linking and site-directed mutagenesis studies. HIV strain drug resistance to inhibitors is a pivotal problem in anti-HIV therapy.