Inhibition of human monoamine oxidase A and B by flavonoids isolated from two Algerian medicinal plants
| Autor: | Khaled M. Elokely, Farida Larit, M. S. Abu-Darwish, Babu L. Tekwani, Manal A. Nael, Yan-Hong Wang, Francisco León, Thomas Efferth, Narayan D. Chaurasiya, Djamila Belouahem-Abed, Samir Benayache, Samira Benyahia, Stephen J. Cutler |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Monoamine Oxidase Inhibitors Monoamine oxidase Drug Evaluation Preclinical Pharmaceutical Science Genistein Mixed inhibition Article Mass Spectrometry Inhibitory Concentration 50 03 medical and health sciences chemistry.chemical_compound Drug Discovery Humans Chrysin Monoamine Oxidase IC50 Cytisus Flavonoids Pharmacology Plants Medicinal Molecular Docking Simulation 030104 developmental biology Complementary and alternative medicine chemistry Biochemistry Docking (molecular) Algeria Molecular Medicine Quercetin Myricetin Hypericum |
| Zdroj: | Phytomedicine. 40:27-36 |
| ISSN: | 0944-7113 |
| Popis: | Background Monoamine oxidases (MAOs) are outer mitochondrial membrane flavoenzymes. They catalyze the oxidative deamination of a variety of neurotransmitters. MAO-A and MAO-B may be considered as targets for inhibitors to treat neurodegenerative diseases and depression and for managing symptoms associated with Parkinson's and Alzheimer's diseases. Purpose The objective was to evaluate the inhibitory effect of Hypericum afrum and Cytisus villosus against MAO-A and B and to isolate the compounds responsible for the MAO-inhibitory activity. Methods The inhibitory effect of extracts and purified constituents of H. afrum and C. villosus were investigated in vitro using recombinant human MAO-A and B, and through bioassay-guided fractionation of ethyl acetate fractions of areal parts of the two plants collected in northeastern Algeria. In addition, computational protein-ligand docking and molecular dynamics simulations were carried out to explain the MAO binding at the molecular level. Results The ethyl acetate (EtOAc) fractions of H. afrum and C. villosus showed the highest MAO inhibition activity against MAO A and B with IC50 values of 3.37 µg/ml and 13.50 µg/ml as well as 5.62 and 1.87 µg/ml, respectively. Bioassay-guided fractionation of the EtOAc fractions resulted in the purification and identification of the known flavonoids quercetin, myricetin, genistein and chrysin as the principal MAO-inhibitory constituents. Their structures were established by extensive 1 and 2D NMR studies and mass spectrometry. Quercetin, myricetin and chrysin showed potent inhibitory activity towards MAO-A with IC50 values of 1.52, 9.93 and 0.25 µM, respectively, while genistein more efficiently inhibited MAO-B (IC50 value: 0.65 µM). The kinetics of the inhibition and the study of dialysis dissociation of the complex of quercetin and myricetin and the isoenzyme MAO-A showed competitive and mixed inhibition, respectively. Both compounds showed reversible binding. Molecular docking experiments and molecular dynamics simulations allowed to estimate the binding poses and to identify the most important residues involved in the selective recognition of molecules in the MAOs enzymatic clefts. Conclusion Quercetin and myricetin isolated from H. afrum together with genistein and chrysin isolated from C. villosus have been identified as potent MAO-A and -B inhibitors. H. afrum and C. villosus have properties indicative of potential neuroprotective ability and may be new candidates for selective MAO-A and B inhibitors. |
| Databáze: | OpenAIRE |
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