Active fragments-guided drug discovery and design of selective tropane alkaloids using ultra-high performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry coupled with virtual calculation and biological evaluation
Active fragments-guided drug discovery and design of selective tropane alkaloids using ultra-high performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry coupled with virtual calculation and biological evaluation
复制标题
使用超高效液相色谱-四极杆飞行时间串联质谱结合虚拟计算和生物学评价，以活性片段为导向的选择性托烷生物碱药物发现和设计
DOI：
10.1007/s00216-016-0043-6
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发表时间：
2017-02
影响因子：
4.3
通讯作者：
白钢
中科院分区：
文献类型：
--
作者：
周梦鸽;马逍遥;孙霁雪;丁国钰;崔庆新;侯媛媛;姜民;白钢
华山参（Physochlaina infundibulatum Kuang）中含有丰富的托烷类生物碱（Tropane alkaloids，TA），对痉挛类型有良好的治疗作用。然而，没有收集到数据来探索毒蕈碱受体亚型的特异性与这些TA的结构之间的关系。为了解决这一问题，建立了基于TA标准品裂解行为的超高效液相色谱-四极杆飞行时间串联质谱（UPLC-Q/TOF-MS）提取离子色谱（EIC）策略，以快速捕获HSS中的各种TA。基于所提供的诊断离子或中性丢失的结构信息，有效地分析了29种TA，特别是一些痕量成分。此外，通过虚拟验证结合分子动力学模拟，发现了大约12种生物碱对毒蕈碱受体具有高选择性。此外，通过在细胞水平上使用双荧光素酶报告分析系统和ACh诱导的体外收缩条试验，选择N-乙酰旋花碱用于M2或M3受体的选择性评价。在总结活性片段和构效关系（SAR）信息的基础上，提出了一种新的修饰TA，该TA具有对M3受体的高亲和性和高选择性，并成功地进行了评价。本研究为基于高选择性药物的天然产物的发现和设计提供了一种有效的方法，该方法结合了虚拟计算和生物学评价技术。图形摘要活性片段指导的HSS选择性抑制剂合成策略
Tropane alkaloids (TAs), rich in the plant ofPhysochlaina infundibularisKuang, which is named Huashanshen (HSS) in China, showed good effects on types of spasms. However, no data were collected to explore the relationship between the specificity for muscarinic receptor subtypes and the structures of these TAs. To address this issue, an extracted ion chromatogram (EIC) strategy using ultra-high performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-Q/TOF-MS) based on the fragmentation behavior of the TA standards was established to rapidly capture the varied TAs from HSS. Based on the provided structural information of diagnostic ions or neutral loss, 29 TAs were efficiently profiled, especially some trace ingredients. In additional, via virtual validation combined with molecular dynamic simulation, approximately a dozen alkaloids were found with high selectivity for muscarinic receptors. In additional, N-acetyl convolicine was chosen for selectivity evaluation of M2or M3receptors through the use of a dual-luciferase reporter assay system at the cellular level and an ACh-induced constricted strip test in vitro. After summarizing the active fragments and the structure-activity relationship (SAR) information, a new modified TA that takes advantage of both the high affinity and high selectivity for M3receptors was proposed and evaluated successfully. This study provided an effective approach for the discovery and design of natural products based on highly selective drugs by UPLC-Q/TOF-MS coupled with virtual calculation and biological evaluation.Graphical AbstractActive fragments-guided strategy for selective inhibitors from HSS
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影响因子：
7.4
作者：
Dennis Klink;O. Schmitz
通讯作者：
Dennis Klink;O. Schmitz
影响因子：
--
作者：
Hu Jingqian;Zhao Bin;Z. Zhe;Dong Jin-gao;Zhang Jinlin
通讯作者：
Hu Jingqian;Zhao Bin;Z. Zhe;Dong Jin-gao;Zhang Jinlin
影响因子：
2.9
作者：
R. Rakwal;G. Agrawal;M. Yonekura
通讯作者：
R. Rakwal;G. Agrawal;M. Yonekura
影响因子：
3.4
作者：
El Bazaoui, Ahmed;Bellimam, My Ahmed;Soulaymani, Abdelmajid
通讯作者：
Soulaymani, Abdelmajid
影响因子：
3.8
作者：
M. Reina;E. Burgueño-Tapia;M. A. Bucio;P. Joseph-Nathan
通讯作者：
M. Reina;E. Burgueño-Tapia;M. A. Bucio;P. Joseph-Nathan