A novel method of aligning molecules by local surface shape similarity.

A novel shape-based method has been developed for overlaying a series of molecule surfaces into a common reference frame. The surfaces are represented by a set of circular patches of approximately constant curvature. Two molecules are overlaid using a clique-detection algorithm to find a set of patches in the two surfaces that correspond, and overlaying the molecules so that the similar patches on the two surfaces are coincident. The method is thus able to detect areas of local, rather than global, similarity. A consensus overlay for a group of molecules is performed by examining the scores of all pairwise overlays and performing a set of overlays with the highest scores. The utility of the method has been examined by comparing the overlaid and experimental configurations of 4 sets of molecules for which there are X-ray crystal structures of the molecules bound to a protein active site. Results for the overlays are generally encouraging. Of particular note is the correct prediction of the 'reverse orientation' for ligands binding to human rhinovirus coat protein HRV14.

SLASH: a program for analysing the functional groups in molecules.

The program SLASH, which is designed to enable large numbers of compounds to be analysed in terms of the functional groups they contain, is described. The usefulness of the groups for analysing the activities of compounds tested in high-throughput biological screens is investigated. The functional group fragments are also studied as a means of determining similarity within groups of compounds.

BOOMSLANG: a program for combinatorial structure generation.

An approach to exploiting pharmacophore models is described. Structures are assembled combinatorially from user-defined fragments and flexibly overlaid into the reference frame of the pharmacophore using distance geometry and molecular mechanics. The match with the pharmacophore is quantified by conformational energy and volume of overlap.