Journal article
Large-scale analysis of water stability in bromodomain binding pockets with grand canonical Monte Carlo
- Abstract:
- Conserved water molecules are of interest in drug design, as displacement of such waters can lead to higher affinity ligands, and in some cases, contribute towards selectivity. Bromodomains, small protein domains involved in the epigenetic regulation of gene transcription, display a network of four conserved water molecules in their binding pockets and have recently been the focus of intense medicinal chemistry efforts. Understanding why certain bromodomains have displaceable water molecules and others do not is extremely challenging, and it remains unclear which water molecules in a given bromodomain can be targeted for displacement. Here we estimate the stability of the conserved water molecules in 35 bromodomains via binding free energy calculations using all-atom grand canonical Monte Carlo simulations. Encouraging quantitative agreement to the available experimental evidence is found. We thus discuss the expected ease of water displacement in different bromodomains and the implications for ligand selectivity.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 1.2MB, Terms of use)
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- Publisher copy:
- 10.1038/s42004-018-0019-x
Authors
+ Engineering and Physical Sciences Research Council
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- Grant:
- EP/J003921/1, EP/L000253/1
- Publisher:
- Springer Nature
- Journal:
- Communications Chemistry More from this journal
- Volume:
- 1
- Pages:
- Article number 19
- Publication date:
- 2018-04-05
- Acceptance date:
- 2018-03-01
- DOI:
- Keywords:
- Pubs id:
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pubs:840559
- UUID:
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uuid:502a1980-9a07-4ea2-b105-0ef963280b28
- Local pid:
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pubs:840559
- Source identifiers:
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840559
- Deposit date:
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2018-04-18
Terms of use
- Copyright holder:
- Aldeghi et al
- Copyright date:
- 2018
- Notes:
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© The Author(s) 2018. This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
- Licence:
- CC Attribution (CC BY)
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