Efficient Search of Chemical Space: Navigating from Fragments to Structurally Diverse Chemotypes

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• 作者：Anne Mai Wassermann ; Peter S. Kutchukian ; Eugen Lounkine ; Tiffany Luethi ; Jacques Hamon ; Michael T. Bocker ; Hasnain A. Malik ; Sandra W. Cowan-Jacob ; Meir Glick
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：November 14, 2013
• 年：2013
• 卷：56
• 期：21
• 页码：8879-8891
• 全文大小：573K
• 年卷期：v.56,no.21(November 14, 2013)
• ISSN：1520-4804

文摘

We introduce a novel strategy to sample bioactive chemical space, which follows-up on hits from fragment campaigns without the need for a crystal structure. Our results strongly suggest that screening a few hundred or thousand fragments can substantially improve the selection of small-molecule screening subsets. By combining fragment-based screening with virtual fragment linking and HTS fingerprints, we have developed an effective strategy not only to expand from low-affinity hits to potent compounds but also to hop in chemical space to substantially novel chemotypes. In benchmark calculations, our approach accessed subsets of compounds that were substantially enriched in chemically diverse hit compounds for various activity classes. Overall, half of the hits in the screening collection were found by screening only 10% of the library. Furthermore, a prospective application led to the discovery of two structurally novel histone deacetylase 4 inhibitors.