Flexible ligand docking using a robust evolutionary algorithm

A flexible ligand docking protocol based on evolutionary algorithms is inve stigated. The proposed approach incorporates family competition and adaptiv e rules to integrate decreasing-based mutations and self-adaptive mutations to act as global and local search strategies, respectively. The method is applied to a dihydrofolate reductase enzyme with the anticancer drug methot rexate and two analogues of antibacterial drug trimethoprim. Conformations and orientations dosed to the crystallographically determined structures ar e obtained, as well as alternative structures with low energy. Numerical re sults indicate that the new approach is very robust. The docked lowest-ener gy structures have root-mean-square derivations ranging from 0.67 to 1.96 A ngstrom with respect to the corresponding crystal structures. (C) 2000 John Wiley & Sons, Inc.