Conformational ensemble comparison for small molecules in drug discovery.

Quantification of three-dimensional similarity between small molecules is a fundamental tool of rational drug design. However, there are no widely-adopted scoring approaches for comparing whole conformational ensembles between molecules. Such scores would be desirable for scenarios in which properties of a molecule have been measured (e.g. activity against a target) but the relevant three dimensional structure is not known. In this study, a set of three complementary ensemble comparison scores is proposed. These are the maximum similarity between any pair of conformations; the proportion of the whole set of the conformations that are matched to within a threshold 3D similarity score; and the average value over these matched conformations of the molecular shape descriptor 'σ-fct', introduced by Ballester et al. The utility of this scoring set is demonstrated in three case studies. The first is an attempt to discriminate between the conformational behaviours of a series of compounds with varying types of cyclisations and other conformationally-significant modifications; the second is an analysis of the more and less active members of a series of GPR119 agonists plus an analysis of a series of orexin-1 antagonists; and the third case study is an attempt to obtain enrichment of active against inactive compounds for a subset of the DUD·E dataset, by ensemble comparison against an active reference compound.