Detailed analysis of grid‐based molecular docking: A case study of CDOCKER—A CHARMm‐based MD docking algorithm

Abstract The influence of various factors on the accuracy of protein‐ligand docking is examined. The factors investigated include the role of a grid representation of protein‐ligand interactions, the initial ligand conformation and orientation, the sampling rate of the energy hyper‐surface, and the final minimization. A representative docking method is used to study these factors, namely, CDOCKER, a molecular dynamics (MD) simulated‐annealing‐based algorithm. A major emphasis in these studies is to compare the relative performance and accuracy of various grid‐based approximations to explicit all‐atom force field calculations. In these docking studies, the protein is kept rigid while the ligands are treated as fully flexible and a final minimization step is used to refine the docked poses. A docking success rate of 74% is observed when an explicit all‐atom representation of the protein (full force field) is used, while a lower accuracy of 66–76% is observed for grid‐based methods. All docking experiments considered a 41‐member protein‐ligand validation set. A significant improvement in accuracy (76 vs. 66%) for the grid‐based docking is achieved if the explicit all‐atom force field is used in a final minimization step to refine the docking poses. Statistical analysis shows that even lower‐accuracy grid‐based energy representations can be effectively used when followed with full force field minimization. The results of these grid‐based protocols are statistically indistinguishable from the detailed atomic dockings and provide up to a sixfold reduction in computation time. For the test case examined here, improving the docking accuracy did not necessarily enhance the ability to estimate binding affinities using the docked structures. © 2003 Wiley Periodicals, Inc. J Comput Chem 13: 1549–1562, 2003