药学学报, 2022, 57(5): 1471-1476
引用本文:
刘爽, 王真真, 谢以清, 龙江兰, 李江玲, 王爱婷, 马强, 鄢丹. 基于序贯分析的绿原酸与头孢噻肟钠相互作用评价[J]. 药学学报, 2022, 57(5): 1471-1476.
LIU Shuang, WANG Zhen-zhen, XIE Yi-qing, LONG Jiang-lan, LI Jiang-ling, WANG Ai-ting, MA Qiang, YAN Dan. Evaluation of interaction of chlorogenic acid and cefotaxime sodium based on sequential analysis[J]. Acta Pharmaceutica Sinica, 2022, 57(5): 1471-1476.

基于序贯分析的绿原酸与头孢噻肟钠相互作用评价
刘爽1,2, 王真真1,2, 谢以清3, 龙江兰1,2, 李江玲2,4, 王爱婷1,2, 马强3*, 鄢丹1,2*
1. 首都医科大学附属北京友谊医院, 北京 100050;
2. 北京市临床药学研究所, 北京 100050;
3. 中国检验检疫科学研究院, 北京 100176;
4. 成都中医药大学药学院, 四川 成都 611137
摘要:
含有绿原酸(chlorogenic acid,CA)的中药注射剂与头孢噻肟钠(cefotaxime sodium,CS)联合用药在临床上时有发生,但药物相容性的科学依据尚薄弱。本研究提出基于等温滴定量热技术、冷喷雾电离质谱技术和抑菌活性测评的序贯分析策略,评价CA与CS分子间相互作用。等温滴定量热实验表明,CA滴定CS时吉布斯自由能ΔG<0且由焓变驱动,提示二者发生了自发化学反应。通过冷喷雾电离质谱发现CA与CS混合后存在结合态特征离子m/z 808.143 5,确认CA与CS发生了化学结合。通过抑菌实验发现,CA可显著降低CS对肺炎克雷伯菌的抑菌能力(P<0.01)。进一步通过分子对接技术表明,CA与CS具有共同作用靶点青霉素结合蛋白3(penicillin binding protein 3,PBP3),提示CA显著降低CS抑菌能力可能与二者竞争性结合PBP3有关。综上,CA可与CS发生自发化学结合并降低其抑菌能力,为绿原酸与头孢噻肟钠相互作用评价提供了研究思路与关键技术。
关键词:    绿原酸      头孢噻肟钠      肺炎克雷伯菌      分子互作      化学结合     
Evaluation of interaction of chlorogenic acid and cefotaxime sodium based on sequential analysis
LIU Shuang1,2, WANG Zhen-zhen1,2, XIE Yi-qing3, LONG Jiang-lan1,2, LI Jiang-ling2,4, WANG Ai-ting1,2, MA Qiang3*, YAN Dan1,2*
1. Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China;
2. Beijing Institute of Clinical Pharmacy, Beijing 100050, China;
3. Chinese Academy of Inspection and Quarantine, Beijing 100176, China;
4. School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
Abstract:
The joint application of traditional Chinese medicine injection containing chlorogenic acid (CA) and cefotaxime sodium (CS) is sometimes appeared in clinical practice, but the scientific basis of drug molecular compatibility is still weak. This study proposes a sequential analysis strategy based on isothermal titration calorimetry (ITC), cold-spray ionization mass spectrometry (CSI-MS) and antibacterial activity test to evaluate the molecular interactions between CA and CS. The results of ITC experiments showed that the Gibbs free energy ΔG < 0 and it was driven by enthalpy change when CA titrated CS, suggesting CA could spontaneously chemically react with CS. Subsequently, the parent ions (m/z 808.143 5) of binding molecular of CA and CS was detected by CSI-MS, indicating CA could chemically bond with CS. Furtherly, the antibacterial experiments found the antibacterial ability of CS against Klebsiella pneumonia was significantly reduced (P < 0.01) by CA in mixed solution. Finally, molecular docking technology showed CA and CS have a common target of penicillin binding protein 3 (PBP3), suggesting that the phenomenon of CA reduced the antibacterial ability of CS may be related to the competitive binding of two components with PBP3. Our studies have shown that CA could spontaneously chemically bond to CS and reduced its antibacterial ability, providing scientific data for molecular interaction evaluation of CA and CS.
Key words:    chlorogenic acid    cefotaxime sodium    Klebsiella pneumoniae    molecular interaction    chemical bonding   
收稿日期: 2021-11-24
DOI: 10.16438/j.0513-4870.2021-1680
基金项目: 国家自然科学基金重点项目(82130112);国家自然科学基金面上项目(81773891);北京市优秀人才“青年拔尖团队”项目(2018000021223TD09);北京市“登峰人才”项目(DFL20190702).
通讯作者: 马强,Tel:86-10-53897463,E-mail:maqiang@caiq.org.cn;鄢丹,Tel:86-10-63139318,E-mail:danyan@ccmu.edu.cn
Email: maqiang@caiq.org.cn;danyan@ccmu.edu.cn
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