The first de novo designed inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase

Bioorg Med Chem Lett. 2006 Jan 1;16(1):88-92. doi: 10.1016/j.bmcl.2005.09.045. Epub 2005 Oct 19.

Abstract

The de novo molecular design program SPROUT has been applied to the X-ray crystal structures of Plasmodium and human dihydroorotate dehydrogenase, respectively. The resulting design templates were used to prepare a series of molecules which, in keeping with predictions, showed useful levels of species-selective enzyme inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimalarials / chemical synthesis*
  • Antimalarials / pharmacology
  • Catalysis
  • Chemistry, Pharmaceutical / methods*
  • Computer Simulation
  • Crystallography, X-Ray
  • Dihydroorotate Dehydrogenase
  • Drug Design*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Kinetics
  • Models, Chemical
  • Models, Molecular
  • Molecular Conformation
  • Oxidoreductases Acting on CH-CH Group Donors / chemistry*
  • Plasmodium falciparum / enzymology*
  • Protein Conformation
  • Software
  • Substrate Specificity
  • Ubiquinone / chemistry

Substances

  • Antimalarials
  • Dihydroorotate Dehydrogenase
  • Enzyme Inhibitors
  • Ubiquinone
  • Oxidoreductases Acting on CH-CH Group Donors