Using a drug repurposing strategy to virtually screen potential HIV-1 entry inhibitors that block the NHR domain of the viral envelope protein gp41

Using a drug repurposing strategy, virtual screening of potential inhibitors of the NHR domain of the HIV-1 gp41 protein, a conserved region critical for the virus-cell membrane fusion and viral infectivity, was carried out. The used computational approach included: (1) molecular docking of this functionally significant region of the HIV-1 envelope with compounds from a library of bioactive molecules containing clinically approved drugs, experimental drugs, and investigational drug candidates; (2) assessing the binding affinity of these compounds to the therapeutic target; (3) molecular dynamics simulations of ligand/NHR-gp41 complexes; (4) calculations of the binding free energy followed by the analysis of molecular dynamics trajectories and selection of compounds promising to test for anti-HIV-1 activity. As a result, six compounds that exhibited the high binding affinity to the NHR domain of the HIV-1 gp41 protein and showed acceptable pharmacological properties were identified. The predicted compounds are assumed to form a promising basis for the development of new, effective and safe broad-spectrum antiviral agents able to inhibit the HIV-1 entry into the host cell.