Assessing the Growth of Bioactive Compounds and Scaffolds over Time: Implications for Lead Discovery and Scaffold Hopping

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• 作者：Swarit Jasial ; Ye Hu ; Jürgen Bajorath
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2016
• 出版时间：February 22, 2016
• 年：2016
• 卷：56
• 期：2
• 页码：300-307
• 全文大小：538K
• ISSN：1549-960X

文摘

The increase in compounds with activity against five major therapeutic target families has been quantified on a time scale and investigated employing a compound–scaffold–cyclic skeleton (CSK) hierarchy. The analysis was designed to better understand possible reasons for target-dependent growth of bioactive compounds. There was strong correlation between compound and scaffold growth across all target families. Active compounds becoming available over time were mostly represented by new scaffolds. On the basis of scaffold-to-compound ratios, new active compounds were structurally diverse and, on the basis of CSK-to-scaffold ratios, often had previously unobserved topologies. In addition, novel targets emerged that complemented major families. The analysis revealed that compound growth is associated with increasing chemical diversity and that current pharmaceutical targets are capable of recognizing many structurally different compounds, which provides a rationale for the rapid increase in the number of bioactive compounds over the past decade. In light of these findings, it is likely that new chemical entities will be discovered for many small molecule targets including relatively unexplored ones as well as for popular and well-studied therapeutic targets. Moreover, given the wealth of new “active scaffolds” that have been increasingly identified for many targets over time, computational scaffold-hopping exercises should generally have a high likelihood of success.