Exploring the binding mode of HIV-1 Vif inhibitors by blind docking, molecular dynamics and MM/GBSA

The lack of a thorough understanding of the Vif-inhibitor complex severely limits the discovery and structure optimization of Vif inhibitors. By employing blind docking, focused docking, MD simulations and MM/GBSA calculations, we found that the binding mode of C10(a) which is located at the BC box domain of Vif, has a good correlation (R-2 = 0.941) between the experimental and the calculated pIC(50). Moreover, all five RN-18 analogues share a common binding pattern to inhibit the degradation of A3G: ring C inserts into the BC box and forms a strong nonpolar interaction with residues Q136, H139 and Y147; ring B is located at the center of the C10 pocket and interacts with A151; ring C lies in the solvent accessible region and interacts with G138. The discovery of the potential HIV Vif-inhibitor binding mode may open up the possibility for rational design of novel ligands specifically targeted towards Vif.