The MPSim-Dock hierarchical docking algorithm: Application to the eight trypsin inhibitor cocrystals

Abstract

To help improve the accuracy of protein–ligand docking as a useful tool for drug discovery, we developed MPSim‐Dock, which ensures a comprehensive sampling of diverse families of ligand conformations in the binding region followed by an enrichment of the good energy scoring families so that the energy scores of the sampled conformations can be reliably used to select the best conformation of the ligand. This combines elements of DOCK4.0 with molecular dynamics (MD) methods available in the software, MPSim. We test here the efficacy of MPSim‐Dock to predict the 64 protein–ligand combinations formed by starting with eight trypsin cocrystals, and crossdocking the other seven ligands to each protein conformation. We consider this as a model for how well the method would work for one given target protein structure. Using as a criterion that the structures within 2 kcal/mol of the top scoring include a conformation within a coordinate root mean square (CRMS) of 1 Å of the crystal structure, we find that 100% of the 64 cases are predicted correctly. This indicates that MPSim‐Dock can be used reliably to identify strongly binding ligands, making it useful for virtual ligand screening.