1)山西医科大学基础医学院,生物化学与分子生物学教研室,出生缺陷与细胞再生山西省重点实验室,太原 030001;2)山西医科大学第二临床医学院,太原 030001;3)山西医科大学第一临床医学院,太原 030001;4)中国科学院广州生物医药与健康研究院,呼吸疾病国家重点实验室,广州 510530
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国家自然科学基金(22007062),山西省高等学校大学生创新创 业训练项目(S2021101140230), 山西省基础研究计划 (202103021224236) 和山西医科大学博士科研启动基金(XD1911) 资助项目。
1)Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Shanxi Medical University, Taiyuan 030001, China;2)The Second Clinical Medical College of Shanxi Medical University ,Taiyuan 030001, China;3)The First Clinical Medical College of Shanxi Medical University ,Taiyuan 030001, China;4)State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
This work was supported by grants from The National Natural Science Foundation of China (22007062), The Innovation and Entrepreneurship Training Project for College Students in Shanxi Province (S2021101140230), the Shanxi Provincial Research Foundation for Basic Research (202103021224236), and Science Research Start-up Fund for Doctor of Shanxi Medical University (XD1911).
目的 从中药筛选具有潜在抑制严重急性呼吸综合征冠状病毒2 (SARS-CoV-2) 活性的成分,进一步从原子水平揭 示其抑制SARS-CoV-2 表面刺突蛋白(S 蛋白) 受体结合域(RBD) 与血管紧张素转化酶2 (ACE2) 结合的内在机制。 方法 检索新型冠状病毒(简称“新冠肺炎”) 治疗中药处方,构建“新冠肺炎中药候选活性成分数据库”。用具有ACE2 抑制活性的小分子化合物构建HipHop药效团模型,并对“新冠肺炎中药候选活性成分数据库”中活性成分筛选。采用分子 对接和分子动力学模拟方法研究候选活性成分与ACE2 的结合方式及其对SARS-CoV-2 S 蛋白与ACE2 识别的影响。 结果 本文通过中药处方挖掘和分子动力学模拟,从143 个新冠肺炎治疗中药处方中筛选出10 种可与SARS-CoV-2 S 蛋白/ 人源ACE2 识别位点结合的中药成分。其中,枇杷叶主要活性成分23-trans-p-coumaryhormentic acid 与ACE2 具有最高的亲和 力,且23-trans-p-coumaryhormentic acid 的结合可有效阻断SARS-CoV-2 S蛋白与宿主细胞ACE2 的结合。结论 本文通过虚 拟筛选发现了SARS-CoV-2 潜在抑制剂分子23-trans-p-coumaryhormentic acid,同时从原子水平预测了其抑制SARS-CoV-2 S 蛋白与ACE2 结合的内在机制,这将为SARS-CoV-2 特异性抗病毒药物的研发提供理论依据。
Objective To detect the active ingredients in the traditional Chinese medicine prescription and its molecular mechanisms against SARS-CoV-2 by prescription mining and molecular dynamics simulations.Methods Herein, prescription mining and virtual screening of drugs were performed to screen the potential inhibitors against SARS-CoV-2. Molecular docking and molecular dynamics (MDs) simulations were further performed to explore the molecular recognition and inhibition mechanism between the potential inhibitors and SARS-CoV-2.Results The natural compounds library was constructed by 143 prescriptions of traditional Chinese medicine, which contained 640 natural compounds. Ten compounds were screened out from the natural compounds library. Among the 10 compounds, 23-trans-p-coumaryhormentic acid, the main active constituent of the Loquat leaf, showed the best binding affinity targeting the recognizing interface of SARS-CoV-2 S protein/ACE2. Upon binding 23-trans-p-coumaryhormentic acid, the key interactions between SARS-CoV-2 S protein and ACE2 were almost interrupted.Conclusion Ten compounds targeting SARS-CoV-2 S protein/ACE2 interface were screened out from natural compound library. And we inferred that 23-trans-p-coumaryhormentic acid is a potential inhibitor against SARS-CoV-2, which would contribute to the development of the antiviral drug for SARS-CoV-2.
张晓铮,高颖,刘玉,邰杨浩,梁力中,张玉龙,侯淑琳,解军.基于处方挖掘与分子动力学模拟筛选严重急性呼吸综合征冠状病毒2潜在抑制剂分子的研究[J].生物化学与生物物理进展,2022,49(10):1889-1900
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