Department of Food and Life Science, Pukyong National University, Busan 48513, Korea.
National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, The University of Mississippi, Oxford, MS 38677, USA.
Mar Drugs. 2021 Jun 4;19(6):326. doi: 10.3390/md19060326.
Phlorotannins are polyphenolic compounds in marine alga, especially the brown algae. Among numerous phlorotannins, dieckol and phlorofucofuroeckol-A (PFF-A) are the major ones and despite a wider biological activity profile, knowledge of the G protein-coupled receptor (GPCR) targets of these phlorotannins is lacking. This study explores prime GPCR targets of the two phlorotannins. In silico proteocheminformatics modeling predicted twenty major protein targets and in vitro functional assays showed a good agonist effect at the α2C adrenergic receptor (αAR) and an antagonist effect at the adenosine 2A receptor (AR), δ-opioid receptor (δ-OPR), glucagon-like peptide-1 receptor (GLP-1R), and 5-hydroxytryptamine 1A receptor (5-THR) of both phlorotannins. Besides, dieckol showed an antagonist effect at the vasopressin 1A receptor (VR) and PFF-A showed a promising agonist effect at the cannabinoid 1 receptor and an antagonist effect at VR. In silico molecular docking simulation enabled us to investigate and identify distinct binding features of these phlorotannins to the target proteins. The docking results suggested that dieckol and PFF-A bind to the crystal structures of the proteins with good affinity involving key interacting amino acid residues comparable to reference ligands. Overall, the present study suggests αAR, AR, δ-OPR, GLP-1R, 5-THR, CBR, and VR as prime receptor targets of dieckol and PFF-A.
岩藻多酚是海洋藻类，尤其是褐藻中的一类多酚化合物。在众多岩藻多酚中，二羟基间苯三酚和岩藻酚芴酮 A（PFF-A）是主要成分，尽管具有更广泛的生物学活性，但人们对这些岩藻多酚的 G 蛋白偶联受体（GPCR）靶点知之甚少。本研究探讨了这两种岩藻多酚的主要 GPCR 靶点。计算机蛋白质化学信息学建模预测了 20 种主要蛋白质靶点，体外功能测定显示，这两种岩藻多酚对α2C 肾上腺素能受体（αAR）具有良好的激动作用，对腺苷 2A 受体（AR）、δ-阿片受体（δ-OPR）、胰高血糖素样肽-1 受体（GLP-1R）和 5-羟色胺 1A 受体（5-THR）具有拮抗作用。此外，二羟基间苯三酚对血管加压素 1A 受体（VR）具有拮抗作用，PFF-A 对大麻素 1 受体具有潜在的激动作用，对 VR 具有拮抗作用。计算机分子对接模拟使我们能够研究和确定这些岩藻多酚与靶蛋白的不同结合特征。对接结果表明，二羟基间苯三酚和 PFF-A 与蛋白质的晶体结构具有良好的亲和力结合，涉及与参考配体可比的关键相互作用氨基酸残基。总的来说，本研究表明 αAR、AR、δ-OPR、GLP-1R、5-THR、CBR 和 VR 是二羟基间苯三酚和 PFF-A 的主要受体靶点。
