Probing the Bioactivity-Relevant Chemical Space of Robust Reactions and Common Molecular Building Blocks

In the search for new bioactive compounds, there is a
trend toward
increasingly complex compound libraries aiming to target the demanding
targets of the future. In contrast, medicinal chemistry and traditional
library design rely mainly on a small set of highly established and
robust reactions. Here, we probe a set of 58 such reactions for their
ability to sample the chemical space of known bioactive molecules,
and the potential to create new scaffolds. Combined with ∼26 000
common available building blocks, the reactions retrieve around 9%
of a scaffold-diverse set of compounds active on human target proteins
covering all major pharmaceutical target classes. Almost 80% of generated
scaffolds from virtual one-step synthesis products are not present
in a large set of known bioactive molecules for human targets, indicating
potential for new discoveries. The results suggest that established
synthesis resources are well suited to cover the known bioactivity-relevant
chemical space and that there are plenty of unexplored regions accessible
by these reactions, possibly providing valuable “low-hanging
fruit” for hit discovery.