期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 59, 期 19, 页码 8787-8803出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b00355
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资金
- EU-COST action Epigenetics: bench to bedside [TD0905]
- EU-FP7REGPOT project INsPiRE [284460]
- SGC
- AbbVie [1097737]
- Bayer
- Boehringer Ingelheim
- Canadian Institutes for Health Research
- Canada Foundation for Innovation
- Genome Canada
- GlaxoSmithKline
- Janssen
- Lilly Canada
- Merck
- Novartis Research Foundation
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Takeda
- Wellcome Trust
- Research Training Group Translational Research Innovation-Pharma (TRIP)
- Else Kroner-Fresenius Foundation (EKFS)
- Cancer Research UK [16417] Funding Source: researchfish
Bromodomain (BRDs) are epigenetic interaction domains currently recognized as emerging drug targets for development of anticancer or anti-inflammatory agents. In this study, development of a selective ligand of the fifth BRD of polybromo protein-1. (PB1(S)) related to switch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complexes is presented. A compound collection was evaluated by consensus virtual screening and a hit was identified. The biophysical study of protein-ligand interactions was performed using X-ray crystallography and isothermal titration calorimetry. Collective data supported the hypothesis that affinity improvement could be achieved by enhancing interactions of the complex with the solvent. The derived SAR along with free energy calculations and a consensus hydration analysis using WaterMap and SZmap algorithms guided rational design of a set of novel analogues. The most potent analogue demonstrated high affinity of 3.3 mu M and an excellent selectivity profile, thus comprising a promising lead for the development of chemical probes targeting PB1(5).
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