Binding Mode Study Of Streptolydigin, An HIV-1 Protease Inhibitor Via Docking Methodology

Streptolydigin is known as an inhibitor of bacterial RNA polymerase while its effect on HIV-1 protease has not been reported before. We found that streptolydigin exhibits an inhibitory activity against HIV-1 protease, but how it acts on the protease is still unknown because no streptolydigin/HIV-1 protease complex is available by now. To explain the inhibitory activity of streptolydigin, we explored the its binding mode via docking methodology.The reliability of the docking method was evaluated by docking Aha006, an HIV-1 protease inhibitor whose binding mode on the protease is already known in to the active site of HIV-1 protease and comparing the docking result and the actual binding mode. Streptolydigin molecule and Aha006 were docked into the active site in the same way. First, streptolydigin and Aha006 were extracted from complexes. Then minimization and quenching processes were employed to get reasonable 3-dimensional conformations of each ligand. To reflect the binding state of inhibitors and receptor more exactly, the flexibility of the active site was taken into consideration. First, we dock the ligands into active site using FlexX, ignoring the flexibility of the protein, to find a rough binding mode of them. Then Flexidock, a docking module considering the flexibility of both inhibitor and receptor, was employed to find a more exact way in which the ligands binding to HIV-1 protease. To determine whether there is a structural water molecule mediating the contacts of ligands and protease, which is observed in reported complexes involving other inhibitors, two different active site models (including or excluding the structural water molecule) were built and each ligand was docked into them respectively. By analyzing the docking result of Aha006, we believe the docking method we used is reliable to predict the binding mode of streptolydigin on HIV-1 protease. The binding result of streptolydigin shows that it binds to the active site of HIV-1 protease in the help of five hydrogen bonds and no water molecule participates in the binding of ligand and receptor. The side chain of Arg8 embraces the inhibitor with the help of a hydrogen bonds involving O-34, playing an important role in stabilizing the complex.