4HMN: Crystal Structure Of Human 17beta-hydroxysteroid Dehydrogenase Type 5 In Complex With (4-(4-chlorophenyl)piperazin-1-yl)(morpholino) Methanone (24)

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.
PDB ID: 4HMNDownload
MMDB ID: 115072
PDB Deposition Date: 2012/10/18
Updated in MMDB: 2013/11
Experimental Method:
x-ray diffraction
Resolution: 2.4  Å
Source Organism:
Similar Structures:
Biological Unit for 4HMN: monomeric; determined by author and by software (PISA)
Molecular Components in 4HMN
Label Count Molecule
Protein (1 molecule)
Aldo-keto Reductase Family 1 Member C3(Gene symbol: AKR1C3)
Molecule annotation
Chemicals (3 molecules)
* Click molecule labels to explore molecular sequence information.

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