Discovery and characterization of naturally occurring potent inhibitors of catechol-O-methyltransferase from herbal medicines.
Discovery and characterization of naturally occurring potent inhibitors of catechol-O-methyltransferase from herbal medicines.
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从草药中发现和表征天然存在的有效儿茶酚-O-甲基转移酶抑制剂
DOI：
10.1039/d0ra10425f
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发表时间：
2021-03-05
期刊：
影响因子：
3.9
通讯作者：
Yang L
中科院分区：
文献类型：
--
作者：
Zhao DF;Fan YF;Wang FY;Hou FB;Gonzalez FJ;Li SY;Wang P;Xia YL;Ge GB;Yang L
人儿茶酚-O-甲基转移酶（hCOMT）由于其在内源性神经递质和外源性药物的代谢失活中的关键作用而被认为是治疗靶点。然而，几乎没有安全有效的COMT抑制剂，并且缺乏结构上的多样性。为了从中药中发现安全有效的hCOMT抑制剂，本研究收集了53种中药产品，并对其抑制hCOMT的作用进行了研究。其中，黄芪（SR）对hCOMT的抑制作用最强，IC 50值为0.75 μg mL−1。为了进一步确定特定化学物质作为COMT抑制剂，建立了亲和超滤-液相色谱-质谱联用方法，并成功应用于鉴定SR提取物中的COMT抑制剂。结果表明，灯盏乙素2、黄芩素9和乳清素A12是有效的COMT抑制剂，显示出高结合指数（>3）和非常低的IC 50值（32.9 ± 3.43 nM、37.3 ± 4.32 nM和18.3 ± 2.96 nM）。抑制动力学和对接模拟结果表明，化合物2、9和12是COMT介导的3-BTD甲基化的有效竞争性抑制剂，并能稳定地与COMT的活性位点结合。这些研究结果表明，亲和超滤允许从复杂的植物提取物基质中快速鉴定天然COMT抑制剂。此外，灯盏乙素2、黄芩素9和oroxylin A 12是SR中hCOMT的有效抑制剂，可作为先导化合物用于开发更有效的非硝基儿茶酚类COMT抑制剂。
Human catechol-O-methyltransferase (hCOMT) is considered a therapeutic target due to its crucial roles in the metabolic inactivation of endogenous neurotransmitters and xenobiotic drugs. There are nevertheless few safe and effective COMT inhibitors and there lacks a diversity in structure. To discover novel safe and effective hCOMT inhibitors from herbal products, in this study, 53 herbal products were collected and their inhibitory effects against hCOMT were investigated. Among them, Scutellariae radix (SR) displayed the most potent inhibitory effect on hCOMT with an IC50 value of 0.75 μg mL−1. To further determine specific chemicals as COMT inhibitors, an affinity ultrafiltration coupled with liquid chromatography-mass spectrometry method was developed and successfully applied to identify COMT inhibitors from SR extract. The results demonstrated that scutellarein 2, baicalein 9 and oroxylin A 12 were potent COMT inhibitors, showing a high binding index (>3) and very low IC50 values (32.9 ± 3.43 nM, 37.3 ± 4.32 nM and 18.3 ± 2.96 nM). The results of inhibition kinetics assays and docking simulations showed that compounds 2, 9 and 12 were potent competitive inhibitors against COMT-mediated 3-BTD methylation, and they could stably bind to the active site of COMT. These findings suggested that affinity ultrafiltration allows a rapid identification of natural COMT inhibitors from a complex plant extract matrix. Furthermore, scutellarein 2, baicalein 9 and oroxylin A 12 are potent inhibitors of hCOMT in SR, which could be used as promising lead compounds to develop more efficacious non-nitrocatechol COMT inhibitors for biomedical applications.
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DOI：
10.1016/j.jchromb.2004.06.045
发表时间：
2004-12-05
期刊：
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
影响因子：
--
作者：
Li HB;Jiang Y;Chen F
通讯作者：
Chen F
影响因子：
4.4
作者：
Patel CN;Georrge JJ;Modi KM;Narechania MB;Patel DP;Gonzalez FJ;Pandya HA
通讯作者：
Pandya HA
影响因子：
4.3
作者：
Cuyas, Elisabet;Verdura, Sara;Menendez, Javier A.
通讯作者：
Menendez, Javier A.
优化8-羟基喹啉作为儿茶酚O-甲基转移酶的抑制剂。
影响因子：
7.3
作者：
Buchler I;Akuma D;Au V;Carr G;de León P;DePasquale M;Ernst G;Huang Y;Kimos M;Kolobova A;Poslusney M;Wei H;Swinnen D;Montel F;Moureau F;Jigorel E;Schulze MED;Wood M;Barrow JC
通讯作者：
Barrow JC
影响因子：
4.6
作者：
Liu Rong-Xiu;Song Guo-Hu;Wei Sheng-Li
通讯作者：
Wei Sheng-Li