Further Development of a Genetic Algorithm for Ligand Docking and Its Application to Screening Combinatorial Libraries
Gareth Jones, Peter Willett, Robert Charles Glen, Andrew R. Leach, Robin Taylor · ACS symposium series · 1999
We have previously reported the development and validation of the program GOLD (Genetic Optimization for Ligand Docking), an automated ligand docking program that uses a genetic algorithm to explore the full range of ligand conformational flexibility with partial flexibility of the protein. The validation of the algorithm exposed certain weaknesses, particularly in its handling of hydrophobic ligands. We describe here a number of modifications designed to overcome these shortcomings. Using the improved algorithm we have investigated the relationship between the program's scoring function and ligand activity and applied the algorithm to screening combinatorial libraries. Using lipase as a target, GOLD docked a library of carboxylic acids and amines extracted from the Fine Chemicals Database. By predicting the binding modes of product from the predicted dockings of reactants the problem is considerably simplified. The success of this approach was verified by comparing the prediction obtained by docking the component reactants with the result obtained by docking the product. The procedure was repeated using a second library of sulphonyl chlorides and amines.