Design, cross-docking and ONIOM studies of potent antiviral HIV-1 nonnucleoside reverse transcriptase inhibitors

Abstract In the present study, we aimed to develop and discover anti-HIV-1 reverse transcriptase (RT) using quinoline as a core structure. Quinoline derivatives were designed using a molecular hybridization approach through the fusion of the pharmacophores present in the structures of HIV-1 RT drugs, namely, nevirapine, efavirenz, etravirine, talviraline, and rilpivirine. Quinoline derivatives were developed into two compounds, namely,4-(2′,6′-dimethyl-4′-cyanophenoxy)-6-(4′′-cyanophenyl)-aminoquinoline (1) and 4-(2′,6′-dimethyl-4′-cyanophenoxy)-2-(4′′-cyanophenyl)-aminoquinoline (2). The binding interactions between nonnucleoside reverse transcriptase inhibitors (NNRTIs), quinoline derivatives and HIV-1 RT were investigated using cross-docking, molecular docking and the ONIOM approach. The cross-docking showed that the conformation of 4G1Q.pdb had the lowest binding energy values compared with the other conformations of HIV-1 RT. The molecular docking and ONIOM results revealed that (2) interacted with LYS101 residues through hydrogen bonding and interacted with TYR181 and TRP229 residues through pi–pi stacking in the binding pocket of HIV-1 RT, similar to that of rilpivirine. Moreover, (2) and rilpivirine had the lowest total interaction energy compared with other ligands. Therefore, the design and development of 2-amino-4-phenoxy-substituted quinoline as an inhibitor of HIV-1 RT is of interest for further study. The data suggested that these novel series could serve as a starting point for the development of anti-HIV-1 drugs in the near future.