Myrianthopoulos, V, Gaboriaud-Kolar, N, Tallant, C et al. (19 more authors) (2016) Discovery and Optimization of a Selective Ligand for the Switch/Sucrose Nonfermenting-Related Bromodomains of Polybromo Protein-1 by the Use of Virtual Screening and Hydration Analysis. Journal of Medicinal Chemistry, 59 (19). pp. 8787-8803. ISSN 0022-2623
Abstract
Bromodomains (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(5)) 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 μM and an excellent selectivity profile, thus comprising a promising lead for the development of chemical probes targeting PB1(5).
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2016 American Chemical Society. This is an open access article under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Arts, Humanities and Cultures (Leeds) > School of Design (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 06 Mar 2019 16:01 |
Last Modified: | 07 Mar 2019 13:46 |
Status: | Published |
Publisher: | American Chemical Society |
Identification Number: | 10.1021/acs.jmedchem.6b00355 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:143333 |