Cross-docking and molecular dynamic studies to achieve the potent antiviral HIV-1 nonnucleoside reverse transcriptase inhibitors

Abstract

Our objective in the present study is to describe and validate the procedures utilized to investigate a quinoline-based compound's potential as an anti-HIV-1 reverse transcriptase (HIV-1 RT) agent. Through the fusion of the pharmacophores found in the structural makeup of HIV-1 RT drugs, the quinoline derivatives 4-(2′,6′-dimethyl-4′-cyanophenoxy)-6-(4′′-cyanophenyl)-aminoquinoline (1) and 4-(2′,6′-dimethyl-4′-cyanophenoxy)-2-(4′′-cyanophenyl)-aminoquinoline (2) have been reported and developed. Using cross-docking, molecular docking, and molecular dynamic approaches, the binding interactions of nonnucleoside reverse transcriptase inhibitors (NNRTIs), quinoline derivatives, and HIV-1 RT were examined. When compared to the other conformations of HIV-1 RT, the cross-docking revealed that the 4G1Q.pdb conformation had the lowest binding energy values. According to the molecular docking evidence, (2) interacted with LYS101 residues by hydrogen bonding and with TYR181 and TRP229 residues via pi-pi stacking in the binding pocket of HIV-1 RT, similar to that of rilpivirine. Furthermore, molecular dynamics simulations showed that the binding affinity of (1) and (2) with HIV-1 RT was quite stable. The stronger binding of HIV-1 RT-(2) in comparison to HIV-1 RT-(1) was further corroborated by the binding free energy determined by MMPBSA and MMGBSA calculations.