Absolute Binding Free Energy Calculations to Improve the Accuracy of Near-Native Ligand Pose Predictions

Abstract

When the high-resolution structure of a protein target is available, molecular docking experiments are commonly used for computer-aided drug discovery. Molecular docking experiments are advantageous since they can provide the binding mode of a molecule in a given target protein as well as the binding affinity. However, despite considerable efforts, accurate prediction of ligand poses bound to a target is still challenging due to the protein's structural flexibility. Recent free energy perturbation molecular dynamics simulation (FEP/MD) calculations have shown that the calculated binding free energies are in good agreement with experimental data for co-crystal benchmark targets. Here, we present an integrated methodology in which initial candidate selection from pose decoys obtained by docking is followed by FEP/MD calculations to improve the accuracy of near-native ligand pose prediction. Our approach is evaluated for the small molecule α-helix mimetics inhibiting protein-protein interactions such as p53-MDMX/MDM2 and BAK-MCL-1. The results demonstrate that using the centroid models of the most populated clusters of docking decoys is an efficient approach to select a small set of ligand conformations in which a near-native pose may be included and applying the FEP/MD method enhances ability in discriminating the near-native ligand conformation from the candidates.