6PSB

Crystal structure of BRD4 bromodomain 1 with N-methylpyrrolidin-2-one (NMP) derivative 18 (5-{[(3R)-1-methyl-5-oxopyrrolidin-3-yl]methyl}-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one)

6PSB の概要

• エントリーDOI: 10.2210/pdb6psb/pdb
• 分子名称: Bromodomain-containing protein 4, 5-{[(3R)-1-methyl-5-oxopyrrolidin-3-yl]methyl}-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one (3 entities in total)
• 機能のキーワード: brd4 bd1, bromodomain, olinone, protein binding
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 15265.53

構造登録者

Ilyichova, O.V.,Scanlon, M.J. (登録日: 2019-07-12, 公開日: 2019-11-27, 最終更新日: 2023-10-11)

主引用文献

Hilton-Proctor, J.P.,Ilyichova, O.,Zheng, Z.,Jennings, I.G.,Johnstone, R.W.,Shortt, J.,Mountford, S.J.,Scanlon, M.J.,Thompson, P.E.
Synthesis and elaboration of N-methylpyrrolidone as an acetamide fragment substitute in bromodomain inhibition.
Bioorg.Med.Chem., 27:115157-115157, 2019

PubMed Abstract: N-Methylpyrrolidone is a solvent molecule which has been shown to compete with acetyl-lysine-containing peptides for binding to bromodomains. From crystallographic studies, it has also been shown to closely mimic the acetamide binding motif in several bromodomains, but has not yet been directly pursued as a fragment in bromodomain inhibition. In this paper, we report the elaboration of N-methylpyrrolidone as a potential lead in fragment-based drug design. Firstly, N-methylpyrrolidone was functionalised to provide points for chemical elaboration. Then, the moiety was incorporated into analogues of the reported bromodomain inhibitor, Olinone. X-ray crystallography revealed that the modified analogues showed comparable binding affinity and structural mimicry to Olinone in the bromodomain binding site.

PubMed: 31727451
DOI: 10.1016/j.bmc.2019.115157

実験手法

X-RAY DIFFRACTION (1.59 Å)