Ph4Dock: Pharmacophore-Based Protein−Ligand Docking

Abstract

The development and validation of the program Ph4Dock is presented. Ph4Dock is a novel automated ligand docking program that makes best use of pharmacophoric features both in a ligand and at concave portions of a protein. By mapping of pharmacophores of the ligand to the pharmacophoric features that represent the concaves of the target protein, Ph4Dock realizes an efficient and accurate prediction of the binding modes between the ligand and the protein. To validate the potential of this unique docking algorithm, we have selected 43 reliable crystal structures of protein−ligand complexes. All of the ligands are druglike, and they are varied in nature. The diffraction-component precision index (DPI) originally used in crystallography was applied in this study in order to evaluate the docking results quantitatively. The root-mean-square deviation (rmsd) between non-hydrogen atoms of the ligand in the prediction and experimental results were analyzed using DPI. The rmsd values for 25 structures, consisting of almost 60% of the dataset, are less than three times of the corresponding DPI values. It means that the precision of docking results obtained by Ph4Dock is mostly equivalent to the experimental error in these cases. The present study has demonstrated that Ph4Dock can accurately reproduce the experimentally determined docking modes if the reliable crystal structures are used. Normally the success rate of the docking is judged using rmsd ≤ 2.0 Å as the criterion. The Ph4Dock marked an appreciably good success rate of 86% based on this criterion.