期刊
CHEMISTRY-A EUROPEAN JOURNAL
卷 23, 期 60, 页码 15227-15232出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201704169
关键词
chemical biology; fragments; molecular diversity; natural products; proteins
资金
- EPSRC [EP/J00894X, EP/N025652/1]
- GSK
- Innovative Medicines Initiative [115489]
- European Union's Seventh Framework Programme
- EFPIA
- AbbVie
- Bayer Pharma AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genome Canada
- Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD] [115766]
- Janssen
- Merck Co.
- Novartis Pharma AG
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- Wellcome Trust [092809/Z/10/Z]
- EPSRC [EP/N025652/1, EP/E020712/1, EP/K039202/1, EP/J00894X/1] Funding Source: UKRI
- Engineering and Physical Sciences Research Council [EP/J00894X/1, EP/K039202/1, EP/E020712/1, EP/N025652/1, 1090024] Funding Source: researchfish
The productive exploration of chemical space is an enduring challenge in chemical biology and medicinal chemistry. Natural products are biologically relevant, and their frameworks have facilitated chemical tool and drug discovery. A top-down synthetic approach is described that enabled a range of complex bridged intermediates to be converted with high step efficiency into 26 diverse sp(3)-rich scaffolds. The scaffolds have local natural product-like features, but are only distantly related to specific natural product frameworks. To assess biological relevance, a set of 52 fragments was prepared, and screened by high-throughput crystallography against three targets from two protein families (ATAD2, BRD1 and JMJD2D). In each case, 3D fragment hits were identified that would serve as distinctive starting points for ligand discovery. This demonstrates that frameworks that are distantly related to natural products can facilitate discovery of new biologically relevant regions within chemical space.
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