Abstract
AIDS, as a lethal disease, is caused by infection with the HIV virus that affects millions of people. Three essential enzymes should be encoded for replication of HIV virus: protease, integrase and reverse transcriptase (RT). RT has two different activities including DNA polymerase and ribonuclease H (RNase H). However, all of the marketed RT inhibitors target only the DNA polymerase activity. Therefore, ribonuclease H activity may serve as a new target for drug discovery. In the present study, a series of 3-Hydroxypyrimidine-2, 4-dione derivatives as potent RT-associated RNase H inhibitors were applied to QSAR analysis. Two methods including multiple linear regressions (MLR) and partial least squared based on genetic algorithm (GA-PLS) were utilized to find the relationship between the structural feathers and inhibitory activities of these compounds. The best multiple linear regression equation was generated by GA-PLS method. A combination of 2D autocorrelations, topological, atom-centered, and geometrical descriptors were selected by GA-PLS as they had more effects on the inhibitory activity. Then, the molecular docking studies were carried out. The results showed that the important amino acids inside the active site of the enzyme responsible for essential interactions were Gln475, Asp549, Tyr501, Ser515, Trp534, Asp493, Tyr472, and Gln480 which took part in hydrogen bond formation. Furthermore, docking energy was plotted against pIC(50) predicted by GA-PLS method. The result showed that there is a good correlation with R(2)=0.71. Consequently, these findings suggest that the better method, GA-PLS, could be applied to design new compounds and predict their inhibitory activity.