Selective Inhibition of Human Monoamine Oxidase B by Acacetin 7-Methyl Ether Isolated from Turnera diffusa (Damiana)

Molecules. 2019 Feb 23;24(4):810. doi: 10.3390/molecules24040810.

Abstract

The investigation of the constituents that were isolated from Turnera diffusa (damiana) for their inhibitory activities against recombinant human monoamine oxidases (MAO-A and MAO-B) in vitro identified acacetin 7-methyl ether as a potent selective inhibitor of MAO-B (IC50 = 198 nM). Acacetin 7-methyl ether (also known as 5-hydroxy-4', 7-dimethoxyflavone) is a naturally occurring flavone that is present in many plants and vegetables. Acacetin 7-methyl ether was four-fold less potent as an inhibitor of MAO-B when compared to acacetin (IC50 = 50 nM). However, acacetin 7-methyl ether was >500-fold selective against MAO-B over MAO-A as compared to only two-fold selectivity shown by acacetin. Even though the IC50 for inhibition of MAO-B by acacetin 7-methyl ether was ~four-fold higher than that of the standard drug deprenyl (i.e., SelegilineTM or ZelaparTM, a selective MAO-B inhibitor), acacetin 7-methyl ether's selectivity for MAO-B over MAO-A inhibition was greater than that of deprenyl (>500- vs. 450-fold). The binding of acacetin 7-methyl ether to MAO-B was reversible and time-independent, as revealed by enzyme-inhibitor complex equilibrium dialysis assays. The investigation on the enzyme inhibition-kinetics analysis with varying concentrations of acacetin 7-methyl ether and the substrate (kynuramine) suggested a competitive mechanism of inhibition of MAO-B by acacetin 7-methyl ether with Ki value of 45 nM. The docking scores and binding-free energies of acacetin 7-methyl ether to the X-ray crystal structures of MAO-A and MAO-B confirmed the selectivity of binding of this molecule to MAO-B over MAO-A. In addition, molecular dynamics results also revealed that acacetin 7-methyl ether formed a stable and strong complex with MAO-B. The selective inhibition of MAO-B suggests further investigations on acacetin 7-methyl as a potential new drug lead for the treatment of neurodegenerative disorders, including Parkinson's disease.

Keywords: Turnera diffusa; acacetin; acacetin 7-methyl ether; molecular docking; molecular dynamics; monoamine oxidase-A; monoamine oxidase-B; neurological disorder.

MeSH terms

  • Binding Sites
  • Flavones / chemistry*
  • Flavones / isolation & purification
  • Humans
  • Inhibitory Concentration 50
  • Kinetics
  • Methyl Ethers / chemistry
  • Methyl Ethers / isolation & purification
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Monoamine Oxidase / metabolism*
  • Monoamine Oxidase Inhibitors / chemistry*
  • Plant Extracts / chemistry*
  • Plant Extracts / isolation & purification
  • Protein Binding
  • Protein Conformation
  • Structure-Activity Relationship
  • Substrate Specificity
  • Turnera / chemistry*

Substances

  • Flavones
  • Methyl Ethers
  • Monoamine Oxidase Inhibitors
  • Plant Extracts
  • Monoamine Oxidase
  • acacetin