Abstract：
BACKGROUND: Cholecystokinin (CCK) is one of the most abundant peptides in the central nervous system and is believed to function as a neurotransmitter as well as a gut hormone with an inverse correlation of its level to anxiety and depression. Therefore, CCK receptors (CCKRs) could be a relevant target for novel antidepressant therapy.
METHODS: In silico target prediction was first employed to predict the probability of the bromophenols interacting with key protein targets based on a model trained on known bioactivity data and chemical similarity considerations. Next, we tested the functional effect of natural bromophenols from Symphyocladia latiuscula on the CCK2 receptor followed by a molecular docking simulation to predict interactions between a compound and the binding site of the target protein.
RESULTS: Results of cell-based functional G-protein coupled receptor (GPCR) assays demonstrate that bromophenols 2,3,6-tribromo-4,5-dihydroxybenzyl alcohol (1), 2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether (2), and bis-(2,3,6-tribromo-4,5-dihydroxybenzyl) ether (3) are full CCK2 antagonists. Molecular docking simulation of 1‒3 with CCK2 demonstrated strong binding by means of interaction with prime interacting residues: Arg356, Asn353, Val349, His376, Phe227, and Pro210. Simulation results predicted good binding scores and interactions with prime residues, such as the reference antagonist YM022.
CONCLUSIONS: The results of this study suggest bromophenols 1-3 are CCK2R antagonists that could be novel therapeutic agents for CCK2R-related diseases, especially anxiety and depression.
METHODS: In silico target prediction was first employed to predict the probability of the bromophenols interacting with key protein targets based on a model trained on known bioactivity data and chemical similarity considerations. Next, we tested the functional effect of natural bromophenols from Symphyocladia latiuscula on the CCK2 receptor followed by a molecular docking simulation to predict interactions between a compound and the binding site of the target protein.
RESULTS: Results of cell-based functional G-protein coupled receptor (GPCR) assays demonstrate that bromophenols 2,3,6-tribromo-4,5-dihydroxybenzyl alcohol (1), 2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether (2), and bis-(2,3,6-tribromo-4,5-dihydroxybenzyl) ether (3) are full CCK2 antagonists. Molecular docking simulation of 1‒3 with CCK2 demonstrated strong binding by means of interaction with prime interacting residues: Arg356, Asn353, Val349, His376, Phe227, and Pro210. Simulation results predicted good binding scores and interactions with prime residues, such as the reference antagonist YM022.
CONCLUSIONS: The results of this study suggest bromophenols 1-3 are CCK2R antagonists that could be novel therapeutic agents for CCK2R-related diseases, especially anxiety and depression.
摘要：
背景：胆囊收缩素（CCK）是中枢神经系统中最丰富的肽之一，被认为是神经递质和肠激素的作用，其水平与焦虑和抑郁呈负相关。因此,CCK受体（CCKRs）可能是新型抗抑郁治疗的相关靶标。
方法：首先采用基于已知生物活性数据和化学相似性考虑的模型的计算机靶标预测来预测溴酚与关键蛋白质靶标相互作用的概率。接下来,我们通过分子对接模拟来预测化合物与靶蛋白结合位点之间的相互作用,测试了天然溴酚对CCK2受体的功能作用.
结果：基于细胞的功能性G蛋白偶联受体（GPCR）测定的结果表明，溴苯酚2,3,6-三溴-4,5-二羟基苯甲醇（1），2,3,6-三溴-4,5-二羟基苄基甲基醚（2），和双-(2,3,6-三溴-4,5-二羟基苄基)醚(3)是完全CCK2拮抗剂。1-3与CCK2的分子对接模拟表明，通过与主要相互作用残基的相互作用，可以实现强结合：Arg356，Asn353，Val349，His376，Phe227和Pro210。模拟结果预测了良好的结合分数和与主要残基的相互作用，如参比拮抗剂YM022。
结论：这项研究的结果表明，溴酚1-3是CCK2R拮抗剂，可能是CCK2R相关疾病的新型治疗剂，尤其是焦虑和抑郁.
方法：首先采用基于已知生物活性数据和化学相似性考虑的模型的计算机靶标预测来预测溴酚与关键蛋白质靶标相互作用的概率。接下来,我们通过分子对接模拟来预测化合物与靶蛋白结合位点之间的相互作用,测试了天然溴酚对CCK2受体的功能作用.
结果：基于细胞的功能性G蛋白偶联受体（GPCR）测定的结果表明，溴苯酚2,3,6-三溴-4,5-二羟基苯甲醇（1），2,3,6-三溴-4,5-二羟基苄基甲基醚（2），和双-(2,3,6-三溴-4,5-二羟基苄基)醚(3)是完全CCK2拮抗剂。1-3与CCK2的分子对接模拟表明，通过与主要相互作用残基的相互作用，可以实现强结合：Arg356，Asn353，Val349，His376，Phe227和Pro210。模拟结果预测了良好的结合分数和与主要残基的相互作用，如参比拮抗剂YM022。
结论：这项研究的结果表明，溴酚1-3是CCK2R拮抗剂，可能是CCK2R相关疾病的新型治疗剂，尤其是焦虑和抑郁.
