张弦　周鑫　尹华　张昊霖　文菲　熊广华　曹德良　廖端芳　傅榕赓

〔摘要〕 目的 基于分子对接探讨水杨酰苯胺化合物Ⅰ-Ⅳ与代谢型谷氨酸受体5（metabotropic glutamate receptor 5， mglu5）之间的相互作用并测定化合物Ⅰ-Ⅳ的体外抗肝癌HepG2细胞增殖活性。方法 采用计算机软件，以mglu5结晶复合物5CGD为受体模板，将水杨酰苯胺化合物Ⅰ-Ⅳ进行分子对接研究；利用MTT法测定水杨酰苯胺化合物Ⅰ-Ⅳ对肝癌HepG2细胞的增殖抑制活性。结果 水杨酰苯胺化合物Ⅰ-Ⅳ与mglu5的活性口袋产生疏水作用以及与活性口袋关键氨基酸残基SER809产生氢键结合；水杨酰苯胺化合物Ⅰ-Ⅳ对肝癌细胞HepG2的抗增殖活性IC50值分别为2.55 μmol/L、3.99 μmol/L、3.12 μmol/L和7.55 μmol/L。结论 水杨酰苯胺化合物Ⅰ-Ⅳ与mglu5对接的结合信息有助于水杨酰苯胺类mglu5拮抗剂的结构优化和新型mglu5拮抗剂设计，该类化合物的抗肿瘤作用值得进一步研究。

〔关键词〕 水杨酰苯胺；代谢型谷氨酸受体5拮抗剂；对接；抗肿瘤

〔中图分类号〕R284.3 〔文献标志码〕A 〔文章编号〕doi：10.3969/j.issn.1674-070X.2018.06.002

〔Abstract〕 Objective To study the interaction between the salicylanilides I-IV with metabotropic glutamate receptor 5 （mglu5） based on molecular docking and their antitumor activity in vitro. Methods The molecular docking study of salicylanilides I-IV were performed by using mglu5 as a receptor template by in silica software. In vitro cytotoxicity of salicylanilides I-IV to human hepatocellular carcinoma cell line HepG2 was measured by a MTT method. Results It was found that salicylanilides I-IV interacted with mglu5 binding site by hydrophobic interaction and a key hydrogen bond with amino acid residue SER809. These interactions were closely related to biological activity. Compounds I-IV showed inhibitory effect on the proliferation of HepG2 cells with the IC50 values of 2.55 μM， 3.99 μmol/L， 3.12 μmol/L and 7.55 μmol/L， respectively. Conclusion The binding information of salicylanilides with mglu5 would be useful for modifying the structure and designing novel mglu5 antagonists. The antitumor activity of compounds of this type would be further studied.

〔Keywords〕 salicylanilide； mglu5 antagonist； docking； antitumor

代謝型谷氨酸受体5（metabotropic glutamate receptor 5， mglu5） 属于G蛋白偶联受体家族的成员，广泛存在于中枢神经系统，并且在多种神经退行性疾病中发挥了至关重要的作用[1]。近年来的研究发现，mglu5不仅存在于脑组织，在许多外周器官和组织中也有表达，mglu5表达及活性的异常还与恶性肿瘤（如肝癌）的发生发展关系密切[2]。因此，

mglu5已成为相关疾病新药研究的热门靶点。

mglu5拮抗剂代表骨架为二芳基类为主的直线型分子[3-4]，而水杨酰苯胺mglu5拮抗剂Ⅰ-Ⅳ（结构如图1所示）是我们课题组前期将水杨酰苯胺这一分子骨架与4-苯胺基喹唑啉类mglu5拮抗剂（代表化合物A）分子骨架进行骨架跃迁，设计合成得到的新型mglu5拮抗剂[5-6]。……