Drug Design, Molecular Docking and Molecular Dynamics Simulations of Indole Class HIV-1 NNRTIs Explored with QSAR and Topomer Search

HIV reverse transcriptase (RT) as one of the key targets for the treatment of HIV, and in recent years a series of indole class non-nucleoside reverse transcriptase inhibitors (NNRTIs) with potent anti-HIV-1 properties have been reported. In this paper, Topomer CoMFA model with reliable validation results (q(2)=0.809, R-2=0.983, R-pred(2)=0.870) for exploring the quantitative structure-activity relationship (QSAR) of the inhibitors. And the relationship between molecular structures and activities were further analysed using the contour plots. The Topomer search technique was employed to search and then designed novel compounds with stronger inhibitory effects. Molecular docking showed that the residue LYS101, GLU138 and ILE180 played a key role, meanwhile, the stability of the docking results was verified by molecular dynamics simulations (MD). Finally, the calculated results of the binding free energy calculations agree with the predictions of the model, further validating the reliability of the proposed model.