3D-QSAR and docking studies on piperidine-substituted diarylpyrimidine analogues as HIV-1 reverse transcriptase inhibitors

In this paper, 65 small molecules of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) were aligned by two different alignment methods (substructure-based and docking-based alignment) for the construction of three-dimensional quantitative structure–activity relationship models. And the molecular descriptors were calculated by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods. Statistical parameters derived from the models using the above two different alignment methods showed that the docking-based CoMFA and CoMSIA models were better than the substructure-based models with both higher internal consistencies ( q 2 of 0.727 and 0.698, respectively) and external predictive powers ( r_pred^2 of 0.906 and 0.940, respectively). According to the generated contour maps, several key structural features required for increasing the biological activity of compounds were achieved. Additionally, a docking study was also performed to explore the binding mechanisms of this series of compounds, and the obtained binding interactions are in agreement with the results of the contour maps. These structural-based and ligand-based computational studies can offer useful references for the further rational design of HIV-1 NNRTIs.