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J Med Chem. 2016 Oct 13;59(19):8787-8803. Epub 2016 Sep 27.

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.

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Department of Pharmacy, University of Athens , Panepistimiopolis Zografou, GR-15771 Athens, Greece.
Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.
Nuffield Department of Clinical Medicine, Target Discovery Institute (TDI), University of Oxford , Roosevelt Drive, Oxford OX3 7BN, U.K.
Schrödinger Inc. , 222 Third Street, Cambridge, Massachusetts 02139, United States.
Genome Damage and Stability Centre, School of Life Sciences, University of Sussex , Brighton BN1 9RQ, U.K.
Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Johann Wolfgang Goethe-University , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
Department of Clinical Therapeutics, School of Medicine, University of Athens , Mikras Asias 75, GR-11527 Athens, Greece.


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).

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