Liaoning University of Traditional Chinese Medicine, Dalian 116600, China.
China Pharmaceutical University, Nanjing 210009, China.
J Chromatogr B Analyt Technol Biomed Life Sci. 2021 Jun 1;1174:122722. doi: 10.1016/j.jchromb.2021.122722. Epub 2021 Apr 23.
The lack of direct connection between traditional herbal medicines and multiple biological targets is a bottleneck in herbal research and quality evaluation. To solve this problem, a strategy for the discovery of active ingredients from function-similar herbal medicines based on multiple biological targets was proposed in this article. The technical route includes chromatographic separation, mass spectrometry analysis, enzymatic activity detection, pharmacophore analysis and molecular docking. Five citrus herbs of Citri Reticulatae Pericarpium (CRP), Citri Exocarpium Rubrum (CER), Citri Grandis Exocarpium (CGE), Aurantii Fructus Immaturus (AFI) and Aurantii Fructus (AF) were used as the research objects. A total of 136 chemical components were identified from above five herbs based on LC-Q-TOF-MS/MS and database matching. The extracts of the five herbs showed obvious inhibitory effects on α-glucosidase and acetylcholinesterase in a concentration-dependent manner. Interestingly, the different types of components in the herbs exhibited selectivity for different targets: flavanone glycosides are effective on α-glucosidase but ineffective on acetylcholinesterase; polymethoxyflavonoids are effective on acetylcholinesterase but ineffective on α-glucosidase. Furthermore, we found for the first time that the components in citrus herbs exhibit opposite structure-activity relationships on the above two targets. For example, the methoxy group can enhance the activity of compounds on acetylcholinesterase but weaken the activity of compounds on α-glucosidase. The selective action is a supplement to the "multi-components, multi-targets" system of herbal medicines. Pharmacophore analysis and molecular docking were applied to explore the interaction between active ingredients and biological targets from the perspective of ligands and receptors, respectively. By combining the above multiple technologies, a strong connection among herbal medicines, chemical components and multiple biological targets was established. This work not only helps to understand the similar function of citrus herbs for the treatment of diabetes and Alzheimer's disease, but also provides selective lead compounds for the development of related drugs. This strategy is also helpful to improve the quality evaluation of citrus herbs from the perspective of biological activity.
传统草药与多个生物靶标之间缺乏直接联系，这是草药研究和质量评价的一个瓶颈。为了解决这个问题，本文提出了一种基于多个生物靶标从功能相似的草药中发现活性成分的策略。该技术路线包括色谱分离、质谱分析、酶活性检测、药效团分析和分子对接。本文以橘红类药材陈皮（CRP）、橘红（CER）、化橘红（CGE）、青皮（AFI）和橘（AF）为研究对象，利用 LC-Q-TOF-MS/MS 结合数据库匹配技术，从上述 5 种药材中共鉴定出 136 个化学成分。这 5 种草药的提取物均表现出明显的抑制α-葡萄糖苷酶和乙酰胆碱酯酶的作用，且呈浓度依赖性。有趣的是，不同类型的成分对不同的靶标具有选择性：黄烷酮糖苷类对α-葡萄糖苷酶有效，而对乙酰胆碱酯酶无效；多甲氧基黄酮类对乙酰胆碱酯酶有效，而对α-葡萄糖苷酶无效。此外，我们首次发现，橘红类药材中的成分在上述两个靶标上表现出相反的构效关系。例如，甲氧基可以增强化合物在乙酰胆碱酯酶上的活性，而削弱其在α-葡萄糖苷酶上的活性。这种选择性作用是对草药“多成分、多靶点”体系的补充。药效团分析和分子对接分别从配体和受体的角度探讨了活性成分与生物靶标的相互作用。通过将上述多种技术相结合，建立了草药、化学成分和多个生物靶标之间的强联系。这项工作不仅有助于理解橘红类药材治疗糖尿病和阿尔茨海默病的相似作用，还为相关药物的开发提供了选择性的先导化合物。该策略还有助于从生物活性的角度提高橘红类药材的质量评价。
