Investigating the extension of pairwise distance pharmacophore measures to triplet-based descriptors

Abstract

Distances between key functional groups have been used for some time as molecular descriptors in 3D database screening and clustering calculations. More recently, a number of groups have explored triplets of molecular centers to describe key ligand features in terms of the properties of triangles. Three-body distances are attractive, since they retain more information than pairwise representations. In most applications, the triangular descriptors have been used to detail molecular shape, using all the constituent atoms or molecular surface points as descriptor centers. As a consequence, the database keying times were such that only single conformers could be considered during molecular descriptor calculations. In this paper we reduce the points used in the molecular description down to the key functional centers, as applied in 3D pharmacophore database searches. Molecular triplets can then be calculated which describe the relative dispositions of differing functional groups, made up from multiple molecular conformations of a given molecule. The new triplet descriptors are compared with classical pairwise distance measures using a variety of pharmacophores, and their potential in database screening, clustering and pharmacophore identification is discussed.