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

Abstract

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 (R² = 0.941) between the experimental and the calculated pIC₅₀. 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.