4HMN
Crystal structure of human 17beta-hydroxysteroid dehydrogenase type 5 in complex with (4-(4-Chlorophenyl)piperazin-1-yl)(morpholino)methanone (24)
Summary for 4HMN
| Entry DOI | 10.2210/pdb4hmn/pdb |
| Descriptor | 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) |
| Functional Keywords | tim-barrel, aldo-keto reductase, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor |
| Biological source | Homo sapiens (human) |
| Cellular location | Cytoplasm: P42330 |
| Total number of polymer chains | 1 |
| Total formula weight | 39092.63 |
| Authors | 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. (deposition date: 2012-10-18, release date: 2013-11-13, Last modification date: 2023-09-20) |
| Primary citation | 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 Cited by 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: 24411201DOI: 10.1016/j.bmc.2013.12.050 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.4 Å) |
Structure validation
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