title: Probing the bioactivity-relevant chemical space of robust reactions and common molecular building blocks.
abstract: 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.
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1, Novartis Campus, CH-4056 Basel, Switzerland. markus.hartenfeller@novartis.com
authors.forename: Markus
authors.initials: M
authors.lastname: Hartenfeller
authors.forename: Martin
authors.initials: M
authors.lastname: Eberle
authors.forename: Peter
authors.initials: P
authors.lastname: Meier
authors.forename: Cristina
authors.initials: C
authors.lastname: Nieto-Oberhuber
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Altmann
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider
authors.forename: Edgar
authors.initials: E
authors.lastname: Jacoby
authors.forename: Steffen
authors.initials: S
authors.lastname: Renner
mesh_terms: D016503:Drug Delivery Systems; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D054852:Small Molecule Libraries / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D054852:Small Molecule Libraries