Selective Interactions of O-Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B

Molecules

RobertJ. Doerksen¹  Jacob Midiwo²  BabuL. Tekwani³  NarayanD. Chaurasiya³  ReginaN. Bwire⁴  Ilias Muhammad⁵  Pankaj Pandey⁵ 

[1] Department of BioMolecular Sciences, Division of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USA;Department of Chemistry, University of Nairobi, Nairobi P.O. Box 30197-00100, Kenya;Department of Infectious Diseases, Division of Drug Discovery, Southern Research, Birmingham, AL 35205, USA;Department of pure and applied Chemistry, Masinde Muliro University of Science and Technology, Kakamega P.O. Box 190-50100, Kenya;National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USA;

关键词: recombinant monoamine oxidase-A;    monoamine oxidase-B;    neurological disorder;    enzyme kinetics;    molecular docking;    inhibition activity;   

DOI  :  10.3390/molecules25225358

来源: DOAJ

【 摘 要 】

A set of structurally related O-methylated flavonoid natural products isolated from Senecio roseiflorus (1), Polygonum senegalense (2 and 3), Bhaphia macrocalyx (4), Gardenia ternifolia (5), and Psiadia punctulata (6) plant species were characterized for their interaction with human monoamine oxidases (MAO-A and -B) in vitro. Compounds 1, 2, and 5 showed selective inhibition of MAO-A, while 4 and 6 showed selective inhibition of MAO-B. Compound 3 showed ~2-fold selectivity towards inhibition of MAO-A. Binding of compounds 1–3 and 5 with MAO-A, and compounds 3 and 6 with MAO-B was reversible and not time-independent. The analysis of enzyme-inhibition kinetics suggested a reversible-competitive mechanism for inhibition of MAO-A by 1 and 3, while a partially-reversible mixed-type inhibition by 5. Similarly, enzyme inhibition-kinetics analysis with compounds 3, 4, and 6, suggested a competitive reversible inhibition of MAO-B. The molecular docking study suggested that 1 selectively interacts with the active-site of human MAO-A near N5 of FAD. The calculated binding free energies of the O-methylated flavonoids (1 and 4–6) and chalcones (2 and 3) to MAO-A matched closely with the trend in the experimental IC_50′s. Analysis of the binding free-energies suggested better interaction of 4 and 6 with MAO-B than with MAO-A. The natural O-methylated flavonoid (1) with highly potent inhibition (IC₅₀ 33 nM; Ki 37.9 nM) and >292 fold selectivity against human MAO-A (vs. MAO-B) provides a new drug lead for the treatment of neurological disorders.

【 授权许可】

Unknown