FLEXIBLE LIGAND DOCKING USING A GENETIC ALGORITHM

Two computational techniques have been developed to explore the orient ational and conformational space of a flexible ligand within an enzyme . Both methods use the Genetic Algorithm (GA) to generate conformation ally flexible ligands in conjunction with algorithms from the DOCK sui te of programs to characterize the receptor site. The methods are appl ied to three enzyme-ligand complexes: dihydrofolate reductase-methotre xate, thymidylate synthase-phenolpthalein and HIV protease-thioketal h aloperidol. Conformations and orientations close to the crystallograph ically determined structures are obtained, as well as alternative stru ctures with low energy. The potential for the GA method to screen a da tabase of compounds is also examined. A collection of ligands is evalu ated simultaneously, rather than docking the ligands individually into the enzyme.