Thao Nguyen Phuong, Luyen Bui Thi Thuy, Lee Ji Sun, Kim Jang Hoon, Kim Young Ho
College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea; Institute of Marine Biochemistry (IMBC), Vietnam Academy of Science and Technology (VAST), 18 Hoang Quoc Viet, Caugiay, Hanoi, Viet Nam.
Department of Pharmaceutical Industry, Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, Viet Nam.
Bioorg Med Chem Lett. 2017 Apr 15;27(8):1874-1879. doi: 10.1016/j.bmcl.2017.02.013. Epub 2017 Feb 9.
The aim of this study was to search for potential therapeutic agents by identifying novel inhibitors of soluble epoxide hydrolase (sEH) from natural plants using an in silico approach. We found that an ethanolic extract from the roots of Cimicifuga dahurica (Turcz.) Maxim. significantly inhibited sEH in vitro. In a phytochemical investigation using assay-guided fractionation of the dichloromethane extract of C. dahurica, we isolated two new indolinone alkaloids (5 and 6) and five related constituents (1-4, and 7) and established their structures based on an extensive analysis using 1D and 2D NMR, and MS methods. All of the isolated compounds inhibited sEH enzymatic activity in a dose-dependent manner, with IC values ranging from 0.8±0.0 to 2.8±0.4μM. A kinetic analysis of compounds 1-7 revealed that compound 2 was non-competitive; 1, 3, and 7 were mixed-type; and 4-6 were competitive inhibitors. Molecular docking was employed to further elucidate their receptor-ligand binding characteristics. These results demonstrated that compounds from C. dahurica are potential sEH inhibitors.
本研究旨在通过计算机模拟方法从天然植物中鉴定可溶性环氧化物水解酶（sEH）的新型抑制剂，以寻找潜在的治疗药物。我们发现，兴安升麻（Cimicifuga dahurica (Turcz.) Maxim.）根的乙醇提取物在体外能显著抑制sEH。在对兴安升麻二氯甲烷提取物进行活性导向分离的植物化学研究中，我们分离出两种新的吲哚酮生物碱（5和6）以及五种相关成分（1 - 4和7），并通过一维和二维核磁共振以及质谱方法进行广泛分析确定了它们的结构。所有分离出的化合物均以剂量依赖性方式抑制sEH酶活性，IC值范围为0.8±0.0至2.8±0.4μM。对化合物1 - 7的动力学分析表明，化合物2为非竞争性抑制剂；1、3和7为混合型抑制剂；4 - 6为竞争性抑制剂。采用分子对接进一步阐明它们的受体 - 配体结合特性。这些结果表明，兴安升麻中的化合物是潜在的sEH抑制剂。
