University of Sussex
Browse
acs.jmedchem jess downs.pdf (6.38 MB)

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

Download (6.38 MB)
journal contribution
posted on 2023-06-09, 09:07 authored by Vassilios Myrianthopoulos, Nicolas Gaboriaud-Kolar, Cynthia Tallant, Michelle-Lynn Hall, Stylianos Grigoriou, Peter Moore Brownlee, Oleg Fedorov, Catherine Rogers, David Heidenreich, Marek Wanior, Nikolaos Drosos, Nikitia Mexia, Pavel Savitsky, Tina Bagratuni, Efstathios Kastritis, Evangelos Terpos, Panagis Filippakopoulos, Susanne Müller, Alexios-Leandros Skaltsounis, Jessica Ann Downs, Stefan Knapp, Emmanuel Mikros
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).

History

Publication status

  • Published

File Version

  • Published version

Journal

Journal of Medicinal Chemistry

ISSN

0022-2623

Publisher

American Chemical Society

Issue

19

Volume

59

Page range

8787-8803

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2017-12-01

First Open Access (FOA) Date

2017-12-01

First Compliant Deposit (FCD) Date

2017-11-30

Usage metrics

    University of Sussex (Publications)

    Categories

    No categories selected

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC