Structural highlights
4hmn is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
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| Ligands: | , , |
| Gene: | AKR1C3, DDH1, HSD17B5, KIAA0119, PGFS (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[AK1C3_HUMAN] Catalyzes the conversion of aldehydes and ketones to alcohols. Catalyzes the reduction of prostaglandin (PG) D2, PGH2 and phenanthrenequinone (PQ) and the oxidation of 9-alpha,11-beta-PGF2 to PGD2. Functions as a bi-directional 3-alpha-, 17-beta- and 20-alpha HSD. Can interconvert active androgens, estrogens and progestins with their cognate inactive metabolites. Preferentially transforms androstenedione (4-dione) to testosterone.
Publication Abstract from PubMed
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 approximately 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.
Morpholylureas are a new class of potent and selective inhibitors of the type 5 17-beta-hydroxysteroid dehydrogenase (AKR1C3).,Flanagan JU, Atwell GJ, Heinrich DM, Brooke DG, Silva S, Rigoreau LJ, Trivier E, Turnbull AP, Raynham T, Jamieson SM, Denny WA Bioorg Med Chem. 2014 Feb 1;22(3):967-77. doi: 10.1016/j.bmc.2013.12.050. Epub, 2014 Jan 2. PMID:24411201[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Flanagan JU, Atwell GJ, Heinrich DM, Brooke DG, Silva S, Rigoreau LJ, Trivier E, Turnbull AP, Raynham T, Jamieson SM, Denny WA. Morpholylureas are a new class of potent and selective inhibitors of the type 5 17-beta-hydroxysteroid dehydrogenase (AKR1C3). Bioorg Med Chem. 2014 Feb 1;22(3):967-77. doi: 10.1016/j.bmc.2013.12.050. Epub, 2014 Jan 2. PMID:24411201 doi:http://dx.doi.org/10.1016/j.bmc.2013.12.050
