Pharmacophore and Docking-based 3D-QSAR Studies on HIV-1 Integrase Inhibitors

Integrase(IN) plays an essential role in the process of HIV-1 replication. IN inhibitors of diketo acid derivatives(DKAs) were analysed by the Comparative Molecular Field Analysis(CoMFA) and Comparative Molecular Similarity Induces Analysis(CoMSIA) methods. A set of 42 compounds were randomly selected as the training set(35) and test set(7). Firstly, a good pharmacophore(goodness of hit=0.787) was obtained and used to align ligands. Then, predictive models were constructed with the CoMFA and CoMSIA methods based on the pharmacophore alignment. As a result, the CoMSIA method yielded the best model with an r² of 0.955 and a q² of 0.665, which can predict the activities of the tested DKAs very well(r²=0.559). Finally, DKAs were docked into IN, and the predicit modes were superimposed on the contour maps obtained from the best CoMSIA model. The superimposed maps gave a visualized and meaningful insight into the inhibitory behaviors, providing significantly useful information for the rational drug design of anti-IN agents.