3D-QSAR Studies on Phthalimide Derivatives as HIV-1 Reverse Transcriptase Inhibitors

The novel non-nucleoside HIV-1 reverse transcriptase inhibitors in a phthalimide series were subjected to the three-dimensional quantitative structure-activity relationship (3D QSAR) studies using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The best predictive CoMFA model gave cross-validated r2 (q2) = 0.688, non-cross-validated r2 = 0.996, included the highest occupied molecular orbital (HOMO) energies in addition to CoMFA fields, and the best predictive CoMSIA model has q2 = 0.629, non-cross-validated r2 = 0.994, included steric, electrostatic, hydrophobic and hydrogen bond acceptor fields. A test set of 12 compounds was used to determine the predictive value of the models. The calculated (predicted) and experimental inhibitory activities were well correlated. The analysis of the 3D contour maps from both CoMFA and CoMSIA models offer important structural insight into designing novel and more active compounds prior to their synthesis.