Novel insights for dihydroorotate dehydrogenase class 1A inhibitors discovery

Eur J Med Chem. 2010 Dec;45(12):5899-909. doi: 10.1016/j.ejmech.2010.09.055. Epub 2010 Oct 7.

Abstract

The enzyme dihydroorotate dehydrogenase (DHODH) has been suggested as a promising target for the design of trypanocidal agents. We report here the discovery of novel inhibitors of Trypanosoma cruzi DHODH identified by a combination of virtual screening and ITC methods. Monitoring of the enzymatic reaction in the presence of selected ligands together with structural information obtained from X-ray crystallography analysis have allowed the identification and validation of a novel site of interaction (S2 site). This has provided important structural insights for the rational design of T. cruzi and Leishmania major DHODH inhibitors. The most potent compound (1) in the investigated series inhibits TcDHODH enzyme with Kiapp value of 19.28 μM and possesses a ligand efficiency of 0.54 kcal mol(-1) per non-H atom. The compounds described in this work are promising hits for further development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Biocatalysis
  • Computational Biology
  • Crystallography, X-Ray
  • Dihydroorotate Dehydrogenase
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Leishmania major / enzymology
  • Ligands
  • Models, Molecular
  • Molecular Sequence Data
  • Molecular Structure
  • Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors*
  • Oxidoreductases Acting on CH-CH Group Donors / chemistry
  • Protein Structure, Tertiary
  • Sequence Alignment
  • Stereoisomerism
  • Structure-Activity Relationship
  • Trypanosoma cruzi / enzymology

Substances

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