Department of Food and Life Science, Pukyong National University, Busan 48513, Korea.
Department of Physics, Pukyong National University, Busan 48513, Korea.
Mar Drugs. 2019 Feb 10;17(2):108. doi: 10.3390/md17020108.
The G protein-coupled receptor (GPCR) family of proteins comprises signaling proteins that mediate cellular responses to various hormones and neurotransmitters, and serves as a prime target for drug discovery. Towards our goal of discovering secondary metabolites from natural sources that can function as neuronal drugs, we evaluated the modulatory effect of eckol on various GPCRs via cell-based functional assays. In addition, we conducted in silico predictions to obtain molecular insights into the functional effects of eckol. Functional assays revealed that eckol had a concentration-dependent agonist effect on dopamine D₃ and D₄ receptors. The half maximal effective concentration (EC) of eckol for the dopamine D₃ and D₄ receptors was 48.62 ± 3.21 and 42.55 ± 2.54 µM, respectively, while the EC values of dopamine as a reference agonist for these two receptors were 2.9 and 3.3 nM, respectively. In silico studies revealed that a low binding energy in addition to hydrophilic, hydrophobic, π⁻alkyl, and π⁻π T-shaped interactions are potential mechanisms by which eckol binds to the dopamine receptors to exert its agonist effects. Molecular dynamics (MD) simulation revealed that Phe346 of the dopamine receptors is important for binding of eckol, similar to eticlopride and dopamine. Our results collectively suggest that eckol is a potential D₃/D₄ agonist for the management of neurodegenerative diseases, such as Parkinson's disease.
G 蛋白偶联受体（GPCR）家族蛋白包含信号蛋白，这些信号蛋白介导细胞对各种激素和神经递质的反应，是药物发现的主要靶点。为了从天然来源中发现可作为神经药物的次级代谢产物，我们通过基于细胞的功能测定评估了表儿茶素对各种 GPCR 的调节作用。此外，我们还进行了计算预测，以获得表儿茶素对功能影响的分子见解。功能测定表明，表儿茶素有浓度依赖性激动剂作用于多巴胺 D₃ 和 D₄ 受体。表儿茶素对多巴胺 D₃ 和 D₄ 受体的半数最大有效浓度（EC₅₀）分别为 48.62 ± 3.21 和 42.55 ± 2.54 µM，而多巴胺作为这两种受体的参考激动剂的 EC 值分别为 2.9 和 3.3 nM。计算研究表明，低结合能以及亲水性、疏水性、π⁻烷基和 π⁻π T 型相互作用是表儿茶素结合多巴胺受体发挥激动作用的潜在机制。分子动力学（MD）模拟表明，多巴胺受体的 Phe346 对表儿茶素的结合很重要，类似于埃替克洛平和多巴胺。我们的研究结果表明，表儿茶素可能是一种潜在的 D₃/D₄ 激动剂，可用于治疗神经退行性疾病，如帕金森病。
