Inhibition of human DHODH by 4-hydroxycoumarins, fenamic acids, and N-(alkylcarbonyl)anthranilic acids identified by structure-guided fragment selection

ChemMedChem. 2010 Apr 6;5(4):608-17. doi: 10.1002/cmdc.200900454.

Abstract

A strategy that combines virtual screening and structure-guided 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 IC(50) values in the low nanomolar range. The structure of human DHODH in complex with an inhibitor of this class is presented.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Hydroxycoumarins / chemical synthesis
  • 4-Hydroxycoumarins / chemistry*
  • 4-Hydroxycoumarins / pharmacology
  • Binding Sites
  • Computer Simulation
  • Drug Discovery
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors*
  • Oxidoreductases Acting on CH-CH Group Donors / metabolism
  • Structure-Activity Relationship
  • ortho-Aminobenzoates / chemical synthesis
  • ortho-Aminobenzoates / chemistry*
  • ortho-Aminobenzoates / pharmacology

Substances

  • 4-Hydroxycoumarins
  • Enzyme Inhibitors
  • ortho-Aminobenzoates
  • fenamic acid
  • Oxidoreductases Acting on CH-CH Group Donors
  • dihydroorotate dehydrogenase
  • 4-hydroxycoumarin