6PS9

Crystal structure of BRD4 bromodomain 1 with N-methylpyrrolidin-2-one (NMP) derivative 17 (5-{2-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]ethyl}-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one)

Summary for 6PS9

• Entry DOI: 10.2210/pdb6ps9/pdb
• Descriptor: Bromodomain-containing protein 4, 5-{2-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]ethyl}-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one (3 entities in total)
• Functional Keywords: brd4 bd1, bromodomain, olinone, protein binding
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 15279.56

Authors

Ilyichova, O.V.,Scanlon, M.J. (deposition date: 2019-07-12, release date: 2019-11-27, Last modification date: 2023-10-11)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.21 Å)