Protostane-type triterpenoids as natural soluble epoxide hydrolase inhibitors: Inhibition potentials and molecular dynamics
Protostane-type triterpenoids as natural soluble epoxide hydrolase inhibitors: Inhibition potentials and molecular dynamics
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原烷型三萜类化合物作为天然可溶性环氧化物水解酶抑制剂：抑制潜力和分子动力学
DOI：
10.1016/j.bioorg.2020.103637
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发表时间：
2020-03-01
影响因子：
5.1
通讯作者：
Ma, Xiao-Chi
中科院分区：
文献类型：
--
作者：
Sun, Cheng-Peng;Zhang, Juan;Ma, Xiao-Chi
抑制可溶性环氧化物水解酶（sEH）是治疗炎症和其他疾病的有前景的治疗方法。本研究从中药中寻找sEH抑制剂，发现泽泻具有抑制sEH的作用。我们构建了一个小型的原甾烷型三萜化合物（1-25）文库。orientale，并筛选其抑菌活性。Alismanin B（1）、11-deoxy-25-anhydro alisol E（4）、11-deoxy alisol B（5）和25-O-ethyl alisol A（15）显示出浓度依赖性的抗sEH活性，IC 50值为3.40 +/- 0.57 μ M至9.57 +/- 0.88 μ M。根据抑制动力学的结果，确定11-脱氧-25-脱水泽泻醇E（4）和11-脱氧泽泻醇B（5）为混合型竞争性抑制剂，Ki值分别为12.6和3.48 μ M。通过分子对接和分子动力学分析了11-脱氧泽泻醇B（5）与sEH的作用机制，发现氨基酸残基Trp 336和Tyr 466是其抑制活性的关键。
The inhibition of soluble epoxide hydrolase (sEH) is a promising therapeutic approach to treat inflammation and other disorders. In our present investigation on searching for sEH inhibitors from traditional Chinese medicines, we found that Alisma orientale displayed inhibition of sEH. We constructed a small library of protostane-type triterpenoids (1-25) isolated from A. orientale, and screened their inhibitory activities. Alismanin B (1), 11-deoxy-25-anhydro alisol E (4), 11-deoxy alisol B (5), and 25-O-ethyl alisol A (15) displayed concentration-dependently inhibitory activities against sEH with IC50 values from 3.40 +/- 0.57 mu M to 9.57 +/- 0.88 mu M. 11-Deoxy-25-anhydro alisol E (4) and 11-deoxy alisol B (5) were defined as mixed-type competitive inhibitors with Ki values of 12.6 and 3.48 mu M, respectively, based on the result of inhibition kinetics. The potential interaction mechanism of 11-deoxy alisol B (5) with sEH was analyzed by molecular docking and molecular dynamics, revealing that amino acid residues Trp336 and Tyr466 were vital for its inhibitory activity.