Flavonoids as inhibitors of human carbonyl reductase 1

Chem Biol Interact. 2008 Jul 30;174(2):98-108. doi: 10.1016/j.cbi.2008.05.021. Epub 2008 May 23.

Abstract

Human carbonyl reductase 1 (CBR1), that is one of the enzymes responsible for the reduced efficiency of treatments by the antineoplastic agents anthracyclines, was functionally expressed in Saccharomyces cerevisiae. CBR1 was purified and kinetically characterised using daunorubicin as substrate. CBR1-catalysed reduction of daunorubicin followed an apparent Michaelis-Menten kinetics with K(M)=85.2+/-26.7microM and V(max)=3490+/-220micromol/(mingprotein). The type of inhibition for the flavonoid compound rutin was determined by studying initial reaction rates in the presence of rutin. The inhibition kinetics was found to follow an apparent mixed inhibition with K(ic)=1.8+/-1.2microM and K(iu)=2.8+/-1.6microM. IC50-values were also determined for a set of flavonoids in order to identify essential structure for inhibition activity. Computational docking experiments of the four best inhibitors to the catalytic site of CBR1 showed that the flavonoid skeleton structure was the binding part of the molecule. The presence of a sugar moiety in 1 and 2, or a sugar mimicking part in 9, directed the orientation of the flavonoid so that the sugars were pointing outwards, giving rise to a stabilising effect to the binding. Finally, additional binding epitopes that interacted with various parts of the flavonoid ligand were identified and could potentially be targeted for further improvement of inhibition activity. These included; hydrogen-binding sites surrounding Ser139 and Cys226, Met234 and Tyr193 or Trp229; aromatic-aromatic interaction with Tyr193, Trp229 or NADPH; van der Waals interactions with Ile140.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Oxidoreductases / antagonists & inhibitors*
  • Antibiotics, Antineoplastic / chemistry
  • Antibiotics, Antineoplastic / metabolism
  • Binding Sites
  • Daunorubicin / chemistry
  • Daunorubicin / metabolism
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism*
  • Flavonoids / chemistry
  • Flavonoids / metabolism*
  • Gene Expression
  • Humans
  • Inhibitory Concentration 50
  • Kinetics
  • Models, Molecular
  • Plant Extracts / chemistry
  • Plant Extracts / metabolism
  • Polymerase Chain Reaction
  • Protein Structure, Tertiary
  • Quercetin / chemistry
  • Quercetin / metabolism
  • Rutin / chemistry
  • Rutin / metabolism
  • Saccharomyces cerevisiae / chemistry
  • Saccharomyces cerevisiae / genetics*
  • Substrate Specificity
  • Transfection

Substances

  • Antibiotics, Antineoplastic
  • Enzyme Inhibitors
  • Flavonoids
  • Plant Extracts
  • Rutin
  • Quercetin
  • Alcohol Oxidoreductases
  • Daunorubicin