Theoretical Study On Diketoacid Inhibitors Of HIV-1Integrase By Computer-Aided Design

The life cycle of HIV-1includes three key enzymes. Integrase (IN) catalyzes the integration of virus DNA into the host DNA and no known analogue of HIV-1IN has been reported in the human cells till now. Therefore, IN is a potential target for anti-AIDS drugs design. Diketo acid inhibitors are the most potent inhibitors of HIV-1IN and only one class of inhibitors to be under clinical trial and FDA-approved. However, lack of complete IN structure and the limitation of its screening method for inhibitors in vitro, blocked the development of drug design based on receptor. So far, only one compound as integrase inhibitors has been used in clinical treatment. The computer aided drug design (CADD) has become the conventional method for drug design and greatly accelerate efficiency of drug development. Based on the existing experimental data, theoretical study on diketoacid inhibitors of HIV-1IN has been performed by computer-aided drug design.The dissertation includes three main parts as follows:1. QSAR analysis was performed on a series of diketoacid (DKA) inhibitors against strand transfer process activity of HIV-1IN. The best model with the most suitable molecule orientation was obtained by using all-space search. The influence of tautomerism (enol and keto) of DKAs, molecular field, charge, alignment rules and other factors on the CoMFA model were considered. The results proved that the enol was the dominant conformation in the HIV-1IN and DKAs complexes. All models indicated favorable internal validation, and CoMFA model seems to be more predictive than that of CoMSIA. The models would give some useful theoretical guidance for the rational design of novel and potent HIV-1integrase inhibitors.2. The QSAR and docking studies were performed to explore the correlation between structure and activity of diketoacid derivative and binding modes of these inhibitors with HIV-1IN. Prototype foamy virus (PFV) IN, a highly homologous protein of HIV-1IN. recently published was used to perform docking study, duing to the absence of a complete DNA-bound HIV IN crystal structure along with two-divalent metals bound in the active site. The result showed that binding modes of most of compounds with IN was similar to that of RAL in PFV IN complex, and electrostatic interaction is an important factor in regulating inhibitor activity. In addition, a new pharmacophore model was established and several compounds with new skeleton were discovered by using the model as a query for virtual screening.3. Molecular dynamics (MD) simulation was performed to explore the structural influence of the double mutations G140S/Q148H of HIV IN on the RAL-IN and EVG-IN complex. The result reviewed that the priming binding site of RAL, the orientation of critical residues in the flexible loop, as well as the hydrogen bonding interactions between RAL and PFV IN were negligibly influenced in the mutated system compared with the wild-type (WT) system. However, the conformational flexibility of this loop resumed sligntly after mutation. Stronger chelation with metal ions, stabilization on flexible loop and free-energy calculations proved that EVG had higher inhibitory activity on strand transfer reaction of IN.