Structure-based virtual screening approach to the discovery of novel inhibitors of factor-inhibiting HIF-1: identification of new chelating groups for the active-site ferrous ion

Bioorg Med Chem. 2009 Nov 15;17(22):7769-74. doi: 10.1016/j.bmc.2009.09.034. Epub 2009 Sep 20.

Abstract

The inhibitors of factor-inhibiting HIF-1 (FIH1) have been shown to be useful as therapeutics for the treatment of anemia. We have been able to identify eight novel FIH1 inhibitors with IC(50) values ranging from 30 to 80microM by means of the virtual screening with docking simulations under consideration of the effects of ligand solvation in the scoring function. The newly identified inhibitors are structurally diverse and have various chelating groups for the active-site ferrous ion including sulfonamide, carboxylate, N-benzo[1,2,5]oxadiazol-4-yl amide, and 2-[1,2,4]triazolo[3,4-b]][1,3,4]thiadiazol-3-yl-quinoline moieties. Each of these four structural classes has not been reported as FIH1 inhibitor, and therefore can be considered for further development by structure-activity relationship or denovo design methods. The interactions with the amino acid residues responsible for the stabilizations of the inhibitors in the active site are addressed in detail.

MeSH terms

  • Algorithms
  • Carboxylic Acids / chemistry
  • Carboxylic Acids / pharmacology
  • Catalytic Domain / drug effects
  • Chelating Agents / pharmacology*
  • Computer Simulation
  • Drug Evaluation, Preclinical*
  • Enzyme Inhibitors / analysis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Ferrous Compounds / chemistry*
  • Ferrous Compounds / metabolism
  • Ions
  • Ligands
  • Mixed Function Oxygenases
  • Quinolines / chemistry
  • Quinolines / pharmacology
  • Repressor Proteins / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology
  • Triazoles / chemistry
  • Triazoles / pharmacology

Substances

  • Carboxylic Acids
  • Chelating Agents
  • Enzyme Inhibitors
  • Ferrous Compounds
  • Ions
  • Ligands
  • Quinolines
  • Repressor Proteins
  • Sulfonamides
  • Triazoles
  • Mixed Function Oxygenases
  • HIF1AN protein, human