Development and evaluation of a generic evolutionary method for protein-ligand docking.

We have developed a generic evolutionary method with an empirical scoring function for the protein-ligand docking, which is a problem of paramount importance in structure-based drug design. This approach, referred to as the GEMDOCK (Generic Evolutionary Method for molecular DOCKing), combines both continuous and discrete search mechanisms. We tested our approach on seven protein-ligand complexes, and the docked lowest energy structures have root-mean-square derivations ranging from 0.32 to 0.99 A with respect to the corresponding crystal ligand structures. In addition, we evaluated GEMDOCK on crossdocking experiments, in which some complexes with an identical protein used for docking all crystallized ligands of these complexes. GEMDOCK yielded 98% docked structures with RMSD below 2.0 A when the ligands were docked into foreign protein structures. We have reported the validation and analysis of our approach on various search spaces and scoring functions. Experimental results show that our approach is robust, and the empirical scoring function is simple and fast to recognize compounds. We found that if GEMDOCK used the RMSD scoring function, then the prediction accuracy was 100% and the docked structures had RMSD below 0.1 A for each test system. These results suggest that GEMDOCK is a useful tool, and may systematically improve the forms and parameters of a scoring function, which is one of major bottlenecks for molecular recognition. Copyright 2004 Wiley Periodicals, Inc. J Comput Chem 25: 843-857, 2004