Prediction of enzyme inhibition (IC50) using a combination of protein–ligand docking and semiempirical quantum mechanics

A set of 77 ligands was constructed for which experimentally determined IC₅₀ values were available. For each of the ligands, prediction of the protein-ligand interaction energy was carried out in two distinct stages. In the first stage, the Protein-Ligand docking program GOLD was used to generate several distinct conformations of the ligand bound to a protein. The geometries of these systems were then optimised using the MOPAC program. A comparison of the relative binding energies of the ligands with the reported IC₅₀ values showed a very poor predictive power. By partitioning the ligand set into two subsets, and eliminating six ligands that were inconsistent with the experimental results, a large increase in accuracy was obtained.