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

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• 作者：Markus Hartenfeller ; Martin Eberle ; Peter Meier ; Cristina Nieto-Oberhuber ; Karl-Heinz Altmann ; Gisbert Schneider ; Edgar Jacoby ; Steffen Renner
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2012
• 出版时间：May 25, 2012
• 年：2012
• 卷：52
• 期：5
• 页码：1167-1178
• 全文大小：578K
• 年卷期：v.52,no.5(May 25, 2012)
• ISSN：1549-960X

文摘

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鈥?00 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 鈥渓ow-hanging fruit鈥?for hit discovery.