Conformational ensemble comparison for small molecules in drug discovery.

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