Similarity searching in files of three-dimensional chemical structures: Flexible field-based searching of molecular electrostatic potentials

Similarity measures based on the molecular electrostatic potential (MEP) have been used to quantify the degree of resemblance between pairs of rigid three-dimensional (3-D) molecules. This paper discusses the effect of including molecular flexibility on the similarities that are calculated using such measures in searches of large 3-D databases. Experiments with a graph-theoretic approach to MEP-based similarity searching demonstrate the limitations of using multiple conformations to represent the variations in an MEP that arise from torsional flexibility. Better results have been obtained with a genetic algorithm (GA) that has been developed for calculating the similarity between the MEPs of pairs of molecules, one or both of which is flexible. Experiments with two small files of flexible 3-D structures show that this GA identifies significantly better alignments than does a comparable GA for searching rigid 3-D molecules.