Biodiversity of small molecules – a new perspective in screening set selection

How is the ‘diversity’ of a compound set defined and how is the most appropriate compound subset identified for assay when screening the entire HTS deck is not an option? A common approach has so far been to cover as much of the chemical space as possible by screening a chemically diverse set of compounds. We show that, rather than chemical diversity, the biologic diversity of a compound library is an essential requirement for hit identification. We describe a simple and efficient approach for the design of a HTS library based on compound–target diversity. Biodiverse compound subsets outperform chemically diverse libraries regarding hit rate and the total number of unique chemical scaffolds present among hits. Specifically, by screening ∼19% of a HTS collection, we expect to discover ∼50–80% of all desired bioactive compounds.

► Biologic diversity of compounds is a key component to molecular diversity.
► Biologic diversity of a library is essential for maximizing hits across targets.
► The DiGS algorithm increases both rate and scaffold diversity of hits.