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ChemMedChem. 2018 May 23;13(10):1051-1057. doi: 10.1002/cmdc.201800030. Epub 2018 Apr 17.

Identifying Small-Molecule Binding Sites for Epigenetic Proteins at Domain-Domain Interfaces.

Author information

1
Structural Genomics Consortium (SGC) & Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford, OX3 7FZ, UK.
2
Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK.
3
Diamond Light Source, Harwell Science and Innovation Campus, Didcot, OX11 0DE, UK.
4
Department of Biochemistry, University of Johannesburg, Auckland Park, 2006, South Africa.
5
Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Johann Wolfgang Goethe University, 60438, Frankfurt am Main, Germany.
6
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.
7
Alzheimer's Research (UK) Oxford Drug Discovery Institute, Nuffield Department of Medicine, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford, OX3 7FZ, UK.

Abstract

Epigenetics is a rapidly growing field in drug discovery. Of particular interest is the role of post-translational modifications to histones and the proteins that read, write, and erase such modifications. The development of inhibitors for reader domains has focused on single domains. One of the major difficulties of designing inhibitors for reader domains is that, with the notable exception of bromodomains, they tend not to possess a well-enclosed binding site amenable to small-molecule inhibition. As many of the proteins in epigenetic regulation have multiple domains, there are opportunities for designing inhibitors that bind at a domain-domain interface which provide a more suitable interaction pocket. Examination of X-ray structures of multiple domains involved in recognising and modifying post-translational histone marks using the SiteMap algorithm identified potential binding sites at domain-domain interfaces. For the tandem plant homeodomain-bromodomain of SP100C, a potential inter-domain site identified computationally was validated experimentally by the discovery of ligands by X-ray crystallographic fragment screening.

KEYWORDS:

X-ray fragment screening; bromodomains; epigenetics; histones; tudor domains

PMID:
29578648
PMCID:
PMC6001751
DOI:
10.1002/cmdc.201800030
[Indexed for MEDLINE]
Free PMC Article

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