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Chemistry. 2017 Oct 26;23(60):15227-15232. doi: 10.1002/chem.201704169. Epub 2017 Oct 6.

Synthesis and Demonstration of the Biological Relevance of sp3 -rich Scaffolds Distantly Related to Natural Product Frameworks.

Author information

1
Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK.
2
School of Chemistry, University of Leeds, Leeds, LS2 9JT, UK.
3
Diamond Light Source Ltd, Harwell Science and Innovation Campus, Didcot, OX11 0QX, UK.
4
Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford, OX3 7DQ, UK.
5
GlaxoSmithKline Medicines Research Centre, Stevenage, SG1 2NY, UK,BenevolentBio, Churchway, London, NW1 1LW, UK.

Abstract

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 sp3 -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.

KEYWORDS:

chemical biology; fragments; molecular diversity; natural products; proteins

PMID:
28983993
PMCID:
PMC5703167
DOI:
10.1002/chem.201704169
[Indexed for MEDLINE]
Free PMC Article

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