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Inhibition of Human DHODH by 4-Hydroxycoumarins, Fenamic Acids, and N-(Alkylcarbonyl)anthranilic Acids Identified by Structure-Guided Fragment Selection

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Author

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.

Publishing year

2010

Language

English

Pages

608-617

Publication/Series

ChemMedChem

Volume

5

Issue

4

Document type

Journal article

Publisher

Wiley-Blackwell

Topic

  • Pharmaceutical Sciences

Keywords

  • Dihydroorotate dehydrogenase
  • drug discovery
  • fragment screening
  • inhibitors
  • structure-activity relationships

Status

Published

ISBN/ISSN/Other

  • ISSN: 1860-7187