Molecular insight into the interaction mechanisms of inhibitors BEC and BEG with HIV-1 protease by using MM-PBSA method and molecular dynamics simulation

HIV-1 protease has been an attractive drug target for the antiretroviral treatment of HIV infection over the years. Molecular dynamics (MD) simulations coupled with Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PB/SA) method have been carried out to investigate the bindings of inhibitors BEC and BEG to HIV-1 protease. The results suggest that van der Waals energies mostly drive the binding of this class of inhibitors to HIV-1 protease. The analyses of structure-affinity relationship by using the free energy decomposition provide a more-detailed insight into the mechanisms driving the bindings of BEC and BEG to HIV-1 protease. It is found that a number of C-H…π and C-H…H-C interactions exist between the hydrophobic groups of BEC and BEG and the hydrophobic residues of the binding pocket in HIV-1 protease, and these interactions and the hydrogen bond interactions of BEC and BEG with HIV-1 protease play important roles in the bindings of BEC and BEG to HIV-1 protease. The improvement and optimization of these interactions are helpful to the rational design of potent inhibitors combating AIDS.