Investigating interactions between HIV-1 gp41 and inhibitors by molecular dynamics simulation and MM-PBSA/GBSA calculations

An approved peptidic HIV-1 fusion inhibitor, T-20, has shown significant promises in clinical applications. However, T-20 must be injected twice daily and is too expensive. Consequently, it is necessary to research oral small molecule HIV-1 fusion inhibitors. In an effort to understand the molecular mechanism of the small molecule inhibitors binding to gp41, we have carried out docking studies, explicit solvent molecular dynamics simulations, and binding free energy calculations. The results of calculated binding free energy are in agreement with the experimental data. Further analysis of the binding free energy components reveals the dominant contributions to hydrophobic interactions. These results could be used to design more effective HIV-1 inhibitors targeted to the hydrophobic pocket of HIV-1 gp41.