Docking-based 3D-QSAR and pharmacophore studies on diarylpyrimidines as non-nucleoside inhibitors of HIV-1 reverse transcriptase

Diarylpyrimidines (DAPYs), a type of effective HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), have been considered as one of the most successful agents for treating AIDS. A number of structurally diverse DAPYs have been designed and synthesized in the past decade, and most of them exhibited potent anti-HIV-1 activities; however, the structure–activity relationships of recently reported DAPYs and their pharmacophore features that interacted with HIV-1 reverse transcriptase (RT) remain to be studied. In the present study, molecular docking studies were first performed on three novel classes of DAPYs to study their binding pattern in the HIV-1 RT. Based on the docking conformations of these DAPYs, 3D-QSAR models were constructed using CoMSIA and Topomer CoMFA methods, and pharmacophore models were also built using distance comparison technique. All selected DAPYs presented preferred U- or L-shaped conformations while being docked into the non-nucleoside inhibitor-binding pocket of the HIV-1 RT. The best CoMSIA model exhibited powerful predictivity, with satisfactory statistical parameters such as a q 2 of 0.572, an r 2 of 0.952, and an r pre 2 of 0.728. Contour maps of the best CoMSIA model were in accordance with those of the Topomer CoMFA model, giving the insight into the feature requirements of DAPYs for the anti-HIV-1 activity. Three potential pharmacophore models were constructed, and each of them was consisted of five hypothesis features. All results suggested that the aromatic ring on the left wing of DAPYs and the central pyrimidine ring contained key pharmacophore features for the anti-HIV-1 activity, and also indicated that the right wing of DAPYs had potential for further structural modification to improve activity. Eight novel DAPY molecules with potential anti-HIV-1 activities were designed on the basis of the obtained results. The findings in this study might provide important information for further design and development of novel HIV-1 NNRTIs. Graphical Abstract