Probing Multi-Target Action of Phlorotannins as New Monoamine Oxidase Inhibitors and Dopaminergic Receptor Modulators with the Potential for Treatment of Neuronal Disorders

• Main Authors: Su Hui Seong, Pradeep Paudel, Jeong-Wook Choi, Dong Hyun Ahn, Taek-Jeong Nam, Hyun Ah Jung, Jae Sue Choi
• Format: Article
• Language: English
• Published: MDPI AG 2019-06-01
• Series: Marine Drugs
• Subjects: phlorotannin; phlorofucofuroeckol-A; dieckol; monoamine oxidase; dopamine receptor; GPCR; computational docking
• Online Access: https://www.mdpi.com/1660-3397/17/6/377

Modulation of multiple protein targets with a single compound is essential for the effective treatment of central nervous system disorders. In our previous G protein-coupled receptor (GPCR) cell-based study, a selective human monoamine oxidase (<i>h</i>MAO)-A inhibitor, eckol, stimulated activity of dopamine D₃ and D₄ receptors. This result led to our interest in marine phlorotannin-mediated modulation of <i>h</i>MAO enzymes and related GPCRs in neuronal disorders. Here, we evaluate the multi-target effects of phloroglucinol, phlorofucofuroeckol-A (PFF-A), and dieckol by screening their modulatory activity against <i>h</i>MAO-A and -B and various neuronal GPCRs. Among the tested phlorotannins, PFF-A showed the strongest inhibitory activity against both <i>h</i>MAO isoforms, with higher selectivity toward <i>h</i>MAO-B than <i>h</i>MAO-A. Enzyme kinetics and docking data revealed that PFF-A noncompetitively acts on <i>h</i>MAOs into the alternative binding pocket of enzymes with allosteric functions. In a functional assay for GPCR screening, dieckol and PFF-A exhibited a multi-target combination of D₃R/D₄R agonism and D₁/5HT_1A/NK₁ antagonism. In particular, they effectively stimulated D₃R and D₄R, compared to other GPCRs. Docking analysis confirmed that dieckol and PFF-A successfully docked into the conserved active sites of D₃R and D₄R and interacted with aspartyl and serine residues in the orthosteric binding pockets of the respective receptors. Based on our experimental and computational data, we established the structure-activity relationship between tested phlorotannins and target proteins, including <i>h</i>MAOs and GPCRs. Our current findings suggest that <i>h</i>MAO inhibitors dieckol and PFF-A, major phlorotannins of edible brown algae with multi-action on GPCRs, are potential agents for treatment of psychological disorders and Parkinson&#8217;s disease.