SUPERPOSITION OF 3-DIMENSIONAL CHEMICAL STRUCTURES ALLOWING FOR CONFORMATIONAL FLEXIBILITY BY A HYBRID METHOD

The superposition of three-dimensional structures is the first task in the evaluation of the largest common three-dimensional substructure o f a set of molecules. This is an important step in the identification of a pharmacophoric pattern for molecules that bind to the same recept or. The superposition method described here combines a genetic algorit hm with a numerical optimization method. A major goal is to adequately address the conformational flexibility of ligand molecules. The genet ic algorithm optimizes in a nondeterministic process the size and the geometric fit of the substructures. The geometric fit is further impro ved by changing torsional angles combining the genetic algorithm and t he directed tweak method. This directed tweak method is based on a num erical quasi-Newton optimization method. Only one starting conformatio n per molecule is necessary. Molecules having several rotatable bends and quite different initial conformations are modified to find large s tructural similarities. A set of angiotensin II antagonists is investi gated to illustrate the performance of the method.