Farida Larit1, Khaled M Elokely2, Narayan D Chaurasiya3, Samira Benyahia4, Manal A Nael2, Francisco León5, Mohammad Sanad Abu-Darwish6, Thomas Efferth7, Yan-Hong Wang3, Djamila Belouahem-Abed8, Samir Benayache9, Babu L Tekwani3, Stephen J Cutler5. 1. Department of BioMolecular Sciences, School of Pharmacy, The University of Mississippi, University, MS 38677, United States; Département de Chimie, Faculté des Sciences Exactes, Université des Frères Mentouri, Constantine, Route d'Aine El Bey 25000, Constantine, Algeria. Electronic address: laritfarida@umc.edu.dz. 2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt. 3. National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS 38677, United States. 4. Laboratoire de Synthèse Organique, Modélisation et Optimisation des Procèdes (LOMOP), Université Badji Mokhtar, Faculté des Sciences, Département de Chimie, 23000 Annaba, Algeria. 5. Department of BioMolecular Sciences, School of Pharmacy, The University of Mississippi, University, MS 38677, United States. 6. Department of Basic and Applied Sciences, Al-Balqa Applied University, Al-Salt 19117, Jordan; Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany. 7. Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany. 8. Institut National De Recherche Forestière, Station de recherche d'El Kala (El Tarf). Algeria. 9. Unité de Recherche Valorisation des Ressources Naturelles, Molécules Bioactives et Analyse Physico-Chimique et Biologique (VARENBIOMOL), Université des Frères Mentouri, Constantine, Route d'Aine El Bey 25000, Constantine, Algeria.
Abstract
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.
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 humanMAO-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 flavonoidsquercetin, 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.
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