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

Wassermann, Anne and Kutchukian, Peter and Lounkine, Eugen and Luethi, Tiffany and Bocker, Michael and Malik, Hasnain and Hamon, Jacques and Jacob, Sandra and Glick, Meir (2013) Efficient Search of Chemical Space: Navigating from Fragments to Structurally Diverse Chemotypes. Journal of Medicinal Chemistry, 56 (21). pp. 8879-8891. ISSN 0022-26231520-4804

Abstract

We introduce a novel strategy to sample the 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 fingerprint, we have developed an effective strategy to not only expand from low-affinity hits to potent compounds but also 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 HDAC4 inhibitors.

Item Type: Article
Date Deposited: 13 Oct 2015 13:13
Last Modified: 04 Jul 2016 23:46
URI: https://oak.novartis.com/id/eprint/11444

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