Abstract:
:Kynurenine monooxygenase (KMO) is a potential drug target for treatment of neurodegenerative disorders such as Huntington's and Alzheimer's diseases. We have evaluated substituted kynurenines as substrates or inhibitors of KMO from Cytophaga hutchinsonii. Kynurenines substituted with a halogen at the 5-position are excellent substrates, with values of kcat and kcat/Km comparable to or higher than kynurenine. However, kynurenines substituted in the 3-position are competitive inhibitors, with KI values lower than the Km for kynurenine. Bromination also enhances inhibition, and 3,5-dibromokynurenine is a potent competitive inhibitor with a KI value of 1.5μM. A pharmacophore model of KMO was developed, and predicted that 3,4-dichlorohippuric acid would be an inhibitor. The KI for this compound was found to be 34μM, thus validating the pharmacophore model. We are using these results and our model to design more potent inhibitors of KMO.
journal_name
Bioorg Med Chem Lettjournal_title
Bioorganic & medicinal chemistry lettersauthors
Phillips RS,Anderson AD,Gentry HG,Güner OF,Bowen JPdoi
10.1016/j.bmcl.2017.02.080subject
Has Abstractpub_date
2017-04-15 00:00:00pages
1705-1708issue
8eissn
0960-894Xissn
1464-3405pii
S0960-894X(17)30223-8journal_volume
27pub_type
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