Cubebin and derivatives as inhibitors of mitochondrial complex I. Proposed interaction with subunit B8

J Enzyme Inhib Med Chem. 2009 Apr;24(2):599-606. doi: 10.1080/14756360802318845.

Abstract

The effects on mitochondrial respiration and complex I NADH oxidase activity of cubebin and derivatives were evaluated. The compounds inhibited the state 3 glutamate/malate-supported respiration of hamster liver mitochondria with IC(50) values ranging from 12.16 to 83.96 microM. NADH oxidase reaction was evaluated in submitochondrial particles. The compounds also inhibited this activity, showing the same order of potency observed for effects on state 3 respiration, as well as a tendency towards a non-competitive type of inhibition (K(I) values ranging from 0.62 to 16.1 microM). A potential binding mode of these compounds with complex I subunit B8, assessed by docking calculations, is proposed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Respiration / drug effects
  • Cricetinae
  • Dose-Response Relationship, Drug
  • Electron Transport Complex I / antagonists & inhibitors*
  • Electron Transport Complex I / chemistry
  • Electron Transport Complex I / metabolism
  • Inhibitory Concentration 50
  • Kinetics
  • Lignans / chemistry*
  • Lignans / pharmacology
  • Mitochondria, Liver / drug effects
  • Mitochondria, Liver / metabolism
  • Models, Molecular
  • Multienzyme Complexes / antagonists & inhibitors
  • Multienzyme Complexes / metabolism
  • NADH, NADPH Oxidoreductases / antagonists & inhibitors
  • NADH, NADPH Oxidoreductases / metabolism
  • Protein Conformation
  • Protein Subunits / chemistry
  • Protein Subunits / metabolism

Substances

  • Lignans
  • Multienzyme Complexes
  • Protein Subunits
  • NADH oxidase
  • NADH, NADPH Oxidoreductases
  • Electron Transport Complex I
  • cubebin