Ab initio molecular simulations based on FMO method for proposing potent inhibitors to reverse transcriptase of HIV

The reverse transcriptase (RT) existing in HIV has been recognized to play an essential role for increasing HIV. It is thus expected that inhibition of the RT activity prevents the increase of HIV. Many types of diarylpyrimidines were synthesized as the inhibitors to RT. Among them, TMC125 and TMC278 were found to play important roles in inhibiting RT activity. In the present study, we picked up some TMC278 derivatives as ligands and investigated the specific interactions between RT and the ligands at atomic and electronic levels, using ab initio fragment molecular orbital (FMO) calculations. First, the derivatives were docked into the ligand-binding pocket of RT using a protein-ligand docking program, and the docked structures were fully optimized in water by a classical molecular mechanics method. Finally, using ab initio FMO calculations, the specific interactions between each amino acid residue of RT and the derivatives were revealed at an electronic level. Based on the FMO results, we proposed some novel inhibitors to RT and demonstrated that one of them binds strongly to RT.