Cluster analysis and three-dimensional QSAR studies of HIV-1 integrase inhibitors.

Three-dimensional quantitative structure-activity relationship (3D QSAR) and cluster analysis were applied to a variety of HIV-1 integrase inhibitors. One structure was chosen from each of 11 classes of inhibitors to represent the whole class in descriptor-based cluster analysis. The 11 classes of inhibitors were classified into two groups. The molecular field analysis (MFA) models for these two clusters had r2 values of 0.90 and 0.95 and q2 values of 0.85 and 0.91 that were noticeably enhanced from those of conventional QSAR models. The five test compounds, which were proposed to have a common binding site near the metal in HIV-1 integrase based on docking studies by Sotriffer et al., were utilized to compare the predictive capability of MFA and conventional QSAR models. Among these five compounds, only L-chicoric acid belongs to cluster 1 and the other four belong to cluster 2. MFA models give better overall predictions and more importantly the activity of these test compounds is better predicted by the MFA model derived from the cluster each test compound belongs to. The necessity of dividing the inhibitors into two groups to obtain predictive QSAR models supports the likelihood of two separate binding sites.