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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ICR Authors

Downs, Jessica

Authors

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

Document Type

Journal Article

Date

2016-10-13

Date Accepted

2016-10-13

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).

Citation

Journal of Medicinal Chemistry, 2016, 59 (19), pp. 8787 - 8803

DOI

10.1021/acs.jmedchem.6b00355

URI

https://repository.icr.ac.uk/handle/internal/5323

Rights

http://creativecommons.org/licenses/by/4.0/

Source Title

Journal of Medicinal Chemistry

Publisher

AMER CHEMICAL SOC

ISSN

0022-2623

eISSN

1520-4804
1520-4804

Collections

Cell and Molecular Biology

Research Team

Genome Stability

Notes