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Probing the bioactivity-relevant chemical space of robust reactions and common molecular building blocks.

Hartenfeller, Markus and Eberle, Martin and Meier, Peter and Nieto-Oberhuber, Cristina and Altmann, Karl-Heinz and Schneider, Gisbert and Jacoby, Edgar and Renner, Steffen (2012) Probing the bioactivity-relevant chemical space of robust reactions and common molecular building blocks. Journal of Chemical Information and Modeling. ISSN 1549-9596

Abstract

In search for new bioactive compounds, there is a trend towards increasingly complex compound libraries aiming to target more 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 10% of a scaffold-diverse set of compounds active on human target proteins over all major pharmaceutical target classes. Enabling new discoveries, almost 80% of newly generated scaffolds from virtual one-step synthesis products are not present in known bioactive molecules for human targets. Our study indicates that established synthesis resources are well suited to cover broadly the known bioactivity relevant chemical space and that there is plenty of unexplored chemical space addressable by these reactions, possibly providing valuable “low-hanging fruits” for hit discovery.

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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/7481

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