期刊
COMMUNICATIONS CHEMISTRY
卷 1, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s42004-018-0019-x
关键词
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资金
- EPSRC
- Evotec via the Systems Approaches to Biomedical Sciences Doctoral Training Center [EP/G037280/1]
- EPSRC UK National Service for Computational Chemistry Software (NSCCS) at Imperial College London [EP/J003921/1]
- EPSRC [EP/L000253/1]
- AbbVie
- Bayer
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Canadian Institutes for Health Research
- Genome Canada
- GlaxoSmithKline
- Janssen
- Lilly Canada
- Novartis Research Foundation
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Takeda
- Wellcome Trust [092809/Z/10/Z]
- SGC
- EPSRC [EP/M022609/1, EP/L000253/1, EP/J010189/1] Funding Source: UKRI
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.
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