Identifying Small‐Molecule Binding Sites for Epigenetic Proteins at Domain–Domain Interfaces |
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| Authors: | Dr David Bowkett Dr Romain Talon Dr Cynthia Tallant Prof Chris Schofield Prof Frank von Delft Prof Stefan Knapp Dr Gordon Bruton Prof Paul E Brennan |
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| Affiliation: | 1. Structural Genomics Consortium (SGC) & Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, NDM Research Building, Oxford, UK;2. Chemistry Research Laboratory, University of Oxford, Oxford, UK;3. Diamond Light Source, Didcot, UK;4. Department of Biochemistry, University of Johannesburg, Auckland Park, South Africa;5. Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Johann Wolfgang Goethe University, Frankfurt am Main, Germany;6. GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire, UK;7. Alzheimer's Research (UK) Oxford Drug Discovery Institute, Nuffield Department of Medicine, University of Oxford, NDM Research Building, Oxford, UK |
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| 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. |
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| Keywords: | bromodomains epigenetics histones tudor domains X-ray fragment screening |
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