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Chemical Space Expansion of Bromodomain Ligands Guided by in Silico Virtual Couplings (AutoCouple)

Batiste, L; Unzue, A; Dolbois, A; Hassler, F; Wang, X; Deerain, N; Zhu, J; ... Caflisch, A; + view all (2018) Chemical Space Expansion of Bromodomain Ligands Guided by in Silico Virtual Couplings (AutoCouple). ACS Central Science , 4 (2) pp. 180-188. 10.1021/acscentsci.7b00401. Green open access

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Abstract

Expanding the chemical space and simultaneously ensuring synthetic accessibility is of upmost importance, not only for the discovery of effective binders for novel protein classes but, more importantly, for the development of compounds against hard-to-drug proteins. Here, we present AutoCouple, a de novo approach to computational ligand design focused on the diversity-oriented generation of chemical entities via virtual couplings. In a benchmark application, chemically diverse compounds with low-nanomolar potency for the CBP bromodomain and high selectivity against the BRD4(1) bromodomain were achieved by the synthesis of about 50 derivatives of the original fragment. The binding mode was confirmed by X-ray crystallography, target engagement in cells was demonstrated, and antiproliferative activity was showcased in three cancer cell lines. These results reveal AutoCouple as a useful in silico coupling method to expand the chemical space in hit optimization campaigns resulting in potent, selective, and cell permeable bromodomain ligands.

Type: Article
Title: Chemical Space Expansion of Bromodomain Ligands Guided by in Silico Virtual Couplings (AutoCouple)
Open access status: An open access version is available from UCL Discovery
DOI: 10.1021/acscentsci.7b00401
Publisher version: https://doi.org/10.1021/acscentsci.7b00401
Language: English
Additional information: This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/10063487
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