Three-dimensional quantitative structure–activity relationship studies on diverse structural classes of HIV-1 integrase inhibitors using CoMFA and CoMSIA

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), three-dimensional quantitative structure–activity relationship (3D-QSAR) techniques, were applied to a set of 89 HIV-1 integrase (IN) inhibitors (training set = 61, test set = 28), belonging to 11 structurally different classes. The biological data for 3′ processing mechanism were used. For CoMFA calculations, three different fitting methods for alignment process were investigated. The best CoMFA model yielded the cross-validated r2 (rcv2) = 0.698 and the non-cross-validated r2 (r2) = 0.947. The derived model indicated the importance of steric (60.8%) as well as electrostatic (39.2%) contributions. For CoMSIA calculations, different combinations of the fields were tested. The best CoMSIA model gave rcv2 = 0.724 and r2 = 0.864. This model showed that steric (30.3%), hydrogen bond donor (43.4%) and hydrogen bond acceptor (26.3%) properties played major roles in HIV-1 IN inhibition. The mapping of hydrogen bond interaction fields with the HIV-1 IN active site gave details on hydrogen bond forming between ligands and enzyme. These obtained results agree well with the experimental observations that there should be hydrogen bond interactions between ligands and Glu152, Lys156 and Lys159 residues. The results not only lead to a better understanding of structural requirements of HIV-1 IN inhibitors but also can help in the design of new IN inhibitors.

Graphical abstract CoMFA and CoMSIA investigations were carried out on 89 HIV-1 integrase inhibitors in order to find the correlation between their molecular fields and biological activities. The results provide information on structural requirements of HIV-1 integrase inhibitors.Figure optionsDownload full-size imageDownload as PowerPoint slide