5NLK

Crystal structure of CREBBP bromodomain complexd with US13A

5NLK の概要

• エントリーDOI: 10.2210/pdb5nlk/pdb
• 分子名称: CREB-binding protein, ~{N}-[3-acetamido-5-[(5-ethanoyl-2-ethoxy-phenyl)carbamoyl]phenyl]furan-2-carboxamide (3 entities in total)
• 機能のキーワード: inhibitor, bromodomain, transferase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm: Q92793
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 14672.81

構造登録者

Zhu, J.,Caflisch, A. (登録日: 2017-04-04, 公開日: 2018-02-21, 最終更新日: 2024-01-17)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.8 Å)