Molecular dynamics simulation and free energy calculations of symmetric fluoro-substituted diol-based HIV-1 protease inhibitors

HIV-1 protease has been an important drug target for the antiretroviral treatment of HIV infection over the years. Molecular dynamics simulations have been carried out to investigate the binding of six inhibitors to HIV-1 protease. The binding free energy of each complex was computed using the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PB/SA) method. Our computations suggest that the fluoro-substitutions result in an increase in van der Waals interaction that dominates the binding free energy of each complex. Comparisons of the inhibitor-residue interactions of the fluoro-substituted inhibitors with the inhibitor BEB reveal that 3-, 2,4- and 2,5-fluoro-substitutions are helpful to combat the drug-resistant mutations on Ile50. The hydrogen bond analyses based on the trajectories of the dynamic simulations show the fluoro-substituted inhibitors can maintain the binding well. These data may assist in designing potent drugs to combat the drug-resistant mutations.