Interrogating dense ligand chemical space with a forward-synthetic library

Abstract

Significance Virtual chemical space, i.e., the set of all conceivable drug-sized molecules, offers an abundance of unexplored quadrants which might contain novel bioactive compounds. Exploring these quadrants has to balance novelty of compounds with their synthetic accessibility. Forward-synthetic databases create novel chemical matter by combining existing and readily available building blocks, thereby biasing the resulting products toward synthesizability. To date, no one has tested whether molecules from such databases can be made in large numbers with an acceptable probability, and we investigated this question here. Moreover, we analyze whether the emerging molecules are binding to a G protein-coupled receptor (GPCR) target and whether ligands can be considered novel in the sense that they represent chemotypes which have not been described for this target before.