Probing the bioactivity-relevant chemical space of robust reactions and common molecular building blocks |
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Authors: | Hartenfeller Markus Eberle Martin Meier Peter Nieto-Oberhuber Cristina Altmann Karl-Heinz Schneider Gisbert Jacoby Edgar Renner Steffen |
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Institution: | Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1, Novartis Campus, CH-4056 Basel, Switzerland. markus.hartenfeller@novartis.com |
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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. |
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