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Article

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

1
National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi, Oxford, MS 38677, USA
2
Department of BioMolecular Sciences, Division of Medicinal Chemistry and Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi, Oxford, MS 38677, USA
*
Authors to whom correspondence should be addressed.
Present address: Department of Infectious Diseases, Division of Drug Discovery, Southern Research, Birmingham, AL 35205, USA.
Received: 29 December 2018 / Revised: 18 February 2019 / Accepted: 19 February 2019 / Published: 23 February 2019
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. View Full-Text
Keywords: acacetin 7-methyl ether; acacetin; monoamine oxidase-A; monoamine oxidase-B; molecular docking; molecular dynamics; neurological disorder; Turnera diffusa acacetin 7-methyl ether; acacetin; monoamine oxidase-A; monoamine oxidase-B; molecular docking; molecular dynamics; neurological disorder; Turnera diffusa
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MDPI and ACS Style

Chaurasiya, N.D.; Zhao, J.; Pandey, P.; Doerksen, R.J.; Muhammad, I.; Tekwani, B.L. Selective Inhibition of Human Monoamine Oxidase B by Acacetin 7-Methyl Ether Isolated from Turnera diffusa (Damiana). Molecules 2019, 24, 810. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24040810

AMA Style

Chaurasiya ND, Zhao J, Pandey P, Doerksen RJ, Muhammad I, Tekwani BL. Selective Inhibition of Human Monoamine Oxidase B by Acacetin 7-Methyl Ether Isolated from Turnera diffusa (Damiana). Molecules. 2019; 24(4):810. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24040810

Chicago/Turabian Style

Chaurasiya, Narayan D., Jianping Zhao, Pankaj Pandey, Robert J. Doerksen, Ilias Muhammad, and Babu L. Tekwani 2019. "Selective Inhibition of Human Monoamine Oxidase B by Acacetin 7-Methyl Ether Isolated from Turnera diffusa (Damiana)" Molecules 24, no. 4: 810. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24040810

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