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.
Date
2016-10-13ICR Author
Author
Myrianthopoulos, V
Gaboriaud-Kolar, N
Tallant, C
Hall, M-L
Grigoriou, S
Brownlee, PM
Fedorov, O
Rogers, C
Heidenreich, D
Wanior, M
Drosos, N
Mexia, N
Savitsky, P
Bagratuni, T
Kastritis, E
Terpos, E
Filippakopoulos, P
Müller, S
Skaltsounis, A-L
Downs, JA
Knapp, S
Mikros, E
Type
Journal Article
Metadata
Show full item recordAbstract
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).
Collections
Subject
Cell Line
Computer Simulation
Crystallography, X-Ray
DNA-Binding Proteins
Drug Design
Humans
Ligands
Models, Molecular
Nuclear Proteins
Protein Binding
Protein Domains
Small Molecule Libraries
Structure-Activity Relationship
Transcription Factors
Research team
Genome Stability
Language
eng
Date accepted
2016-10-13
License start date
2016-10-13
Citation
Journal of Medicinal Chemistry, 2016, 59 (19), pp. 8787 - 8803
Publisher
AMER CHEMICAL SOC
Except where otherwise noted, this item's license is described
as
http://creativecommons.org/licenses/by/4.0/
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