Inhibition of Human DHODH by 4-Hydroxycoumarins, Fenamic Acids, and N-(Alkylcarbonyl)anthranilic Acids Identified by Structure-Guided Fragment Selection
Författare
Summary, in English
A strategy that combines virtual screening and structureguided selection of fragments was used to identify three unexplored classes of human DHODH inhibitor compounds: 4-hydroxycoumarins, fenamic acids, and N-(alkylcarbonyl)anthranilic acids. Structure-guided selection of fragments targeting the inner subsite of the DHODH ubiquinone binding site made these findings possible with screening of fewer than 300 fragments in a DHODH assay. Fragments from the three inhibitor classes identified were subsequently chemically expanded to target an additional subsite of hydrophobic character. All three classes were found to exhibit distinct structure–activity relationships upon expansion. The novel N-(alkylcarbonyl anthranilic acid class shows the most promising potency against human DHODH, with IC50 values in the low nanomolar range. The structure of human DHODH in complex with an inhibitor of this class is presented.
Publiceringsår
2010
Språk
Engelska
Sidor
608-617
Publikation/Tidskrift/Serie
ChemMedChem
Volym
5
Issue
4
Dokumenttyp
Artikel i tidskrift
Förlag
Wiley-Blackwell
Ämne
- Pharmaceutical Sciences
Nyckelord
- Dihydroorotate dehydrogenase
- drug discovery
- fragment screening
- inhibitors
- structure-activity relationships
Status
Published
ISBN/ISSN/Övrigt
- ISSN: 1860-7187