5NLK

Crystal structure of CREBBP bromodomain complexd with US13A

Summary for 5NLK

• Entry DOI: 10.2210/pdb5nlk/pdb
• Descriptor: CREB-binding protein, ~{N}-[3-acetamido-5-[(5-ethanoyl-2-ethoxy-phenyl)carbamoyl]phenyl]furan-2-carboxamide (3 entities in total)
• Functional Keywords: inhibitor, bromodomain, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: Q92793
• Total number of polymer chains: 1
• Total formula weight: 14672.81

Authors

Zhu, J.,Caflisch, A. (deposition date: 2017-04-04, release date: 2018-02-21, Last modification date: 2024-01-17)

Primary citation

Batiste, L.,Unzue, A.,Dolbois, A.,Hassler, F.,Wang, X.,Deerain, N.,Zhu, J.,Spiliotopoulos, D.,Nevado, C.,Caflisch, A.
Chemical Space Expansion of Bromodomain Ligands Guided by in Silico Virtual Couplings (AutoCouple).
ACS Cent Sci, 4:180-188, 2018

PubMed 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.

PubMed: 29532017
DOI: 10.1021/acscentsci.7b00401

Experimental method

X-RAY DIFFRACTION (1.8 Å)