would be beneficial if the model can be used to determine which compounds will retain potency against these resistant mutants. Selection experiments with the INSTI MK 2048 yielded an integrase carrying the G118R mutation . In the model of HIV 1 IN, G118 is close to the active site residue D116. Moreover, the C Dabigatran is oriented such that the arginine side chain would extend directly toward the D116 side chain and the magnesium ion that it binds. When this mutation is introduced into the model in silico, the arginine side chain forces the entire backbone to rotate. This would perturb a favorable Van der Waals contact between DTG and the C of G118 seen in the docked and crystal structures. Based on our model, the G118R mutation should rease the IC50 of DTG to 190 nM, representing nearly a 6 fold rease over the IC50 of WT IN.
The in vitro activity ofDTGagainst this mutant has not been reported, but this Human immunodeficiency virus type 1 integrase is an essential enzyme for splicing a viral DNA replica of its genome into host cell chromosomal DNA and has been recently RAAS System recognized as a promising therapeutic target for developing anti AIDS agents. The interaction between HIV 1 IN and vDNA plays an important role in the integration process of the virus. However, a detailed understanding about the mechanism of this interactions as well as the action of the anti HIV drug raltegravir targeting HIV 1 IN in the inhibition of the vDNA strand transfer is still absent.
In the present work, a molecular modeling study by combining homology modeling, molecular dynamics simulations with molecular mechanics Poisson–Boltzmann objectified surface area , and molecular mechanics Generalized Born surface area calculations was performed to investigate the molecular mechanism of HIV 1 IN–vDNA interactions and the inhibition action of vDNA strand transfer inhibitor RAL. The structural analysis showed that RAL did not influence the interaction between vDNA and HIV 1 IN, but rather targeted a special conformation of HIV 1 IN to compete with host DNA and block the function of HIV 1 IN by forcing the 30 OH of the terminal A17 nucleotide away from the three catalytic residues and two Mg2þ ions. Thus, the obtained results could be helpful for understanding of the integration process of the HIV 1 virus and provide some new clues for the rational design and discovery of potential compounds that would specifically block HIV 1 virus replication Integration of the viral DNA into the host cell chromosomal DNA is a crucial step in the human immunodeficiency virus type 1 life cycle.
This integrated DNA can be used immediately to build more viruses, or it can stay dormant, waiting for the best time to start virus production. This is one of the reasons that HIV is so hard to fight: it can lie to wait in these long lived cells for years. Previous studies have demonstrated that the role of integration reaction involves two steps: 30 processing and strand transfer. In the 30 processing reaction, the HIV 1 integrase protein removes two nucleotides from each 30 end of the vDNA, leaving recessed CA hydroxyl group at the 30 end. In the strand transfer reaction, the IN protein joins the previously 30 end to the 50 end of strands of hDNA at the site of integration. HIV 1 IN is a 32 kDa enzyme of 288.