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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).

Original publication

DOI

10.1021/acs.jmedchem.6b00355

Type

Journal article

Journal

Journal of medicinal chemistry

Publication Date

10/2016

Volume

59

Pages

8787 - 8803

Addresses

Department of Pharmacy, University of Athens , Panepistimiopolis Zografou, GR-15771 Athens, Greece.

Keywords

Cell Line, Humans, Nuclear Proteins, Transcription Factors, Ligands, Crystallography, X-Ray, Protein Binding, Structure-Activity Relationship, Drug Design, Models, Molecular, Computer Simulation, Small Molecule Libraries, Protein Domains