Study On The Interactions Between HIV-1 Integrase And Inhibitors With Molecular Modeling

With the completion of Human Genome Project (HGP), the post-genomic era focusing on the functional genomics and proteomics researches has already come. Studies on the relationship between protein structure and function, and its actual application are important parts of the proteomics research. Protein molecules play crucial roles in the life activities through recognition and interactions with ligand molecules. These interactions are the necessary prerequisites for gene regulation, signal transduction, immunoreaction etc. Therefore, the studies of the interactions between protein receptor and ligand are important for understanding biological regulation mechanism, and cellular structure and function, which will also provide the theory foundation for designing and discovering new drug targets. The study of the interactions and recognition between protein and ligand is one of the pioneering and hot themes in life science field all the time.Since determining protein structures with experimental approach is still challenging, recently, with the continuous progress in computers'processing ability and the rapid development and extensive application of theoretical simulation, molecular modeling methods, such as molecular dynamics (MD), molecular docking and free energy computation, have become important tools for exploring the interaction process of protein with ligand. Molecular modeling not only enables us to understand and reveal the essence of life phenomena in the level of molecule, subunit or even atom, but also provides strong theoretical support to experimental results. With the improvement of molecular modeling theory and technology advances, molecular modeling methods are increasingly being used in the research of protein structure-function relationship, protein-ligand mutual recognition, as well as rational drug design.The prevalence of AIDS dramatically threatens human life health, which makes the drug design against AIDS as a hot field and many countries are spending huge money on it. Human immunodeficiency virus (HIV) integrase (IN) is an important target for designing and developing the novel anti-HIV drug. In the life cycle of HIV, IN aids the integration of viral DNA into the host chromosome. Consequently, the study on the recognition mechanism of IN with inhibitors is important for the design and modification of the anti-HIV drugs. In the first part of this dissertation, the binding modes of HIV-1 IN with the benzoic acid inhibitor D77 is explored, and the inhibitory mechanism of this inhibitor is explained. In the second part of this dissertation, a complex structure of HIV IN and DNA was constructed and this complex model can be used in virtual screening or other receptor-based drug design. The main content of this dissertation includes the following two parts:1. Study on inhibitory mechanism and binding mode of the benzoic acid derivative D77 to HIV-1 integraseThe binding modes of the wild type IN core domain and the two mutants, that is, W131A, with the benzoic acid derivative D77 were first obtained by using the"relaxed complex"molecular docking approach combined with MD simulations. Through the comparison between the complex modes of D77 with the wild type IN and the W131A mutant, it was found that the binding modes of D77 with the two systems are quite different. This is mainly because of the non-conserved substitution of the W131 with A131. When substituted by alanine, the benzene ring 1 of D77 leans to the long side-chain of the W132, thus causing the shift of the binding mode of D77. According to the simulation results, it was found that D77 can not only block the binding of LEDGF/p75 to IN, it can also affect the stability of the 150-167 peptide which is important for the mutual recognition of IN with viral DNA. According to the MM-GBSA energy decomposition, W131, W132 and E170 identified as key residues in the binding of D77.2. Study on the binding modes of the HIV integrase-DNA complex to Some integrase inhibitors with molecular modelingIn the current work, a model for complex of IN and viral DNA was built by combining experimental data with the results of molecular dynamics simulation. According to the results of molecular docking, the inhibitors of the second group share a similar binding model with those of the first group, though they have no common scaffold. This suggests these inhibitors may share a similar inhibitory mechanism. In principle, these compounds coordinate the Mg2+ ion with their DKA-like moieties and make hydrophobic interactions with a pocket around the 140s loop with their halogenated-benzene moieties. All main findings of this work are in good accordance with previous experiment or simulation works and the newly built model of the IN-DNA complex is helpful for our subsequent research on the design of IN inhibitors.