4HMN

Crystal structure of human 17beta-hydroxysteroid dehydrogenase type 5 in complex with (4-(4-Chlorophenyl)piperazin-1-yl)(morpholino)methanone (24)

4HMN の概要

• エントリーDOI: 10.2210/pdb4hmn/pdb
• 分子名称: Aldo-keto reductase family 1 member C3, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, [4-(4-chlorophenyl)piperazin-1-yl](morpholin-4-yl)methanone, ... (5 entities in total)
• 機能のキーワード: tim-barrel, aldo-keto reductase, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P42330
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 39092.63

構造登録者

Turnbull, A.P.,Flanagan, J.U.,Atwell, G.J.,Heinrich, D.M.,Jamieson, S.M.F.,Brooke, D.G.,Silva, S.,Rigoreau, L.J.M.,Trivier, E.,Soudy, C.,Samlal, S.S.,Owen, P.J.,Schroeder, E.,Raynham, T.,Denny, W.A. (登録日: 2012-10-18, 公開日: 2013-11-13, 最終更新日: 2023-09-20)

主引用文献

Flanagan, J.U.,Atwell, G.J.,Heinrich, D.M.,Brooke, D.G.,Silva, S.,Rigoreau, L.J.,Trivier, E.,Turnbull, A.P.,Raynham, T.,Jamieson, S.M.,Denny, W.A.
Morpholylureas are a new class of potent and selective inhibitors of the type 5 17-beta-hydroxysteroid dehydrogenase (AKR1C3).
Bioorg.Med.Chem., 22:967-977, 2014

PubMed Abstract: Inhibitors of the aldo-keto reductase enzyme AKR1C3 are of interest as potential drugs for leukemia and hormone-related cancers. A series of non-carboxylate morpholino(phenylpiperazin-1-yl)methanones were prepared by palladium-catalysed coupling of substituted phenyl or pyridyl bromides with the known morpholino(piperazin-1-yl)methanone, and shown to be potent (IC50∼100nM) and very isoform-selective inhibitors of AKR1C3. Lipophilic electron-withdrawing substituents on the phenyl ring were positive for activity, as was an H-bond acceptor on the other terminal ring, and the ketone moiety (as a urea) was essential. These structure-activity relationships are consistent with an X-ray structure of a representative compound bound in the AKR1C3 active site, which showed H-bonding between the carbonyl oxygen of the drug and Tyr55 and His117 in the 'oxyanion hole' of the enzyme, with the piperazine bridging unit providing the correct twist to allow the terminal benzene ring to occupy the lipophilic pocket and align with Phe311.

PubMed: 24411201
DOI: 10.1016/j.bmc.2013.12.050

実験手法

X-RAY DIFFRACTION (2.4 Å)