Insights into the key structural features of N1-ary-benzimidazols as HIV-1 NNRTIs using molecular docking, molecular dynamics, 3D-QSAR, and pharmacophore modeling

N-1-ary-benzimidazol (NABZ) derivatives, an important class of HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs), have been considered as one of the most successful agents for treating with AIDS at present. However, their three-dimensional quantitative structure-activity relationship (3D-QSAR) and mechanism of action in the HIV-1 reverse transcriptase (RT) have not been well understood. In this paper, 38 NABZs were firstly docked into the binding pocket of the HIV-1 RT to elucidate their interaction mechanism, and molecular dynamics simulations were then carried out to confirm the reliability of the docking results. The docking-based 3D-QSAR models were generated using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods to give insights into the key structural features of NABZs for their activity. Both models yield satisfactory statistical parameters of the internal and external validation, and the CoMSIA model (Q(2)=0.670, R-2=0.987, and rpred2 = 0.954) showed slightly better predictive ability than the CoMFA model (Q(2)=0.613, R-2=0.985, and rpred2 = 0.939). The graphical contours demonstrated that the sulfonyl linker was a significant bridge for binding to the HIV-1 RT. The constructed pharmacophore with eight key features further verified the docking and 3D-QSAR results, indicating that the hydrogen-bond acceptor groups at the C-4-positon of the arylacetamide moiety were important for the anti-HIV-1 activity, in addition to 3,5-dimethylphenyl, benzimidazole, and arylacetamide moieties. These studies might provide significant insights into the key structural features for designing potent HIV-1 NNRTIs.