CN111402968A - 基于分子模拟发现山柰酚在covid-19病毒中的新用途 - Google Patents
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Abstract
本发明涉及基于分子模拟发现山柰酚在COVID‑19病毒中的新用途，发明人以COVID‑19的3CL主蛋白酶为靶标蛋白，从含有57278个中药小分子TCM的数据库中，虚拟筛选出了化合物山柰酚，通过山柰酚在细胞水平的抗新型冠状病毒实验，发明人发现山柰酚在62.50‑125.00µg/ml的浓度范围内对新型冠状病毒感染Vero E6细胞致细胞病变具有显著的抑制作用，这一发现从治疗靶标分析角度为中医药抗新型冠状病毒的科学性和潜在疗效提供了佐证。
Description
技术领域
本发明涉及生物技术领域，具体涉及基于分子模拟发现山柰酚在COVID-19病毒中的新用途。
背景技术
2019年12月，一种新型冠状病毒（COVID-19,又名2019-nCoV）在一批患者中被发现。患者表现出类似于中东呼吸综合征冠状病毒（MERS-CoV）和严重急性呼吸综合征冠状病毒（SARS-CoV）的病毒性肺炎症状。目前尚未有药物被批准专门用于COVID-19感染。随着COVID-19在世界范围持续蔓延，研发广谱抗冠状病毒药物和疫苗成为全球公共卫生、医学界、科研界的一个重大挑战。
冠状病毒主蛋白酶（Mpro，又叫3CLpro）是一种蛋白水解酶，可以水解加工复制酶前体多聚蛋白，并释放病毒RNA复制所需的聚合酶与解螺旋酶，是病毒复制过程中的关键步骤。3CLpro在病毒生命周期中的重要作用使其成为开发广谱抗冠状病毒药物的重要靶标蛋白。
近期，饶子和团队解析了COVID-19的3CL主蛋白酶 (COVID-19 3CLpro)的晶体结构（PDB ID：6LU7）。其活性位点结构以及基因序列与SARS-CoV 3CLpro 的非常相近，说明二者可能有相似的抑制机制。发明人曾基于SARS冠状病毒主蛋白酶（SARS-CoV 3CLpro）的蛋白活性位点设计了一种八肽AVLQSGFR（专利申请号200410018679.3，名称为“一种抑制冠状病毒的多肽及其衍生物”），并证明了计算机辅助虚拟筛选出的八肽制剂对SARS病毒有一定的抑制作用。相关筛选流程和实验方法为本发明的研究技术基础。
山柰酚（kaempferol）又名百蕊草素Ⅲ，属于黄酮类化合物，大量临床研究表明，其具有抗炎、抗氧化、抗菌等广泛的药理作用。具体结构如下：
山柰酚是否可以作为抗COVID-19病毒药物，对抗COVID-19病毒是否能起到有效作用，目前还尚未有文献提及。
发明内容
本发明的目的在于提供基于分子模拟发现山柰酚在COVID-19病毒中的新用途，以COVID-19 3CL主蛋白酶为靶标蛋白，通过药物虚拟筛选得到山柰酚，并用实验证明其对COVID-19感染细胞的致细胞病变效应具有显著的抑制作用。
为了实现上述目的，本发明提供的技术方案如下：
基于分子模拟发现山柰酚在COVID-19病毒中的新用途。
发明人进行了以下实验：
1、以中药小分子TCM数据库为对接配体库进行虚拟筛选。
2、根据对接得分进行排序并获得前5名化合物的小分子结构。
3、选取山柰酚进行抗病毒实验验证，评价其对COVID-19感染的细胞病变作用。
其中，虚拟筛选以COVID-19的3CL主蛋白酶为靶标蛋白，HIS41和CYS145为对接活性口袋。
其中，化合物山柰酚从中药小分子TCM数据库中虚拟筛选而出。
其中，山柰酚在62.50-125.00µg/ml的浓度范围内对新型冠状病毒感染Vero E6细胞致细胞病变具有显著的抑制作用。
本发明的有益效果是：发明人通过虚拟筛选和抗病毒实验，首次发现了山柰酚在62.50-125.00µg/ml的浓度范围内对COVID-19感染Vero E6细胞的致细胞病变具有显著的抑制作用。这一发现从治疗靶标分析角度为中医药抗新型冠状病毒的科学性和潜在疗效提供了佐证。
附图说明
图1为药物筛选前五名化合物的二维描述及其对接得分图。
图2为山柰酚对COVID-19药效检测结果图。
具体实施方式
以下结合附图和具体实施例对本发明作具体的介绍。
本发明所用到的虚拟筛选软件为SAMM(Shanghai Molecular Modelling)。2019-nCoV受试药物为山柰酚粉末，所用到的细胞为VeroE6细胞，由广州呼吸健康研究院呼吸疾病国家重点实验室病毒室保存，病毒为SARS-COV-2，滴度为TCID50 = 10-6/100 μL，由广州海关技术中心BSL-3实验室（呼吸疾病国家重点实验室高致病病原微生物研究室）-80℃保存，使用病毒滴度为100TCID50。
实施例1，虚拟筛选。实验以COVID-19 3CLpro为靶标蛋白（PDB ID：6LU7），其三维结构数据来源于PDB数据库。配体数据来源于 TCM Database@Taiwa (http://tcm.cmu.edu.)获取的中药小分子和发明人自建的中药化学数据库，进行对接的中药小分子数共计 57278 个。对接前先按照Lipinski类药五规则进行初步筛选，所得小分子需满足以下五个条件条件：（1）分子量小于500；（2）氢键给体数目小于5；（3）氢键受体数目小于10；（4）脂水分配系数小于5；（5）可旋转键的数量不超过10个。对接使用SAMM软件，对接前用对靶标蛋白进行预处理，包括蛋白质加氢、计算电荷、添加原子类型。对接参考发明人已设计的八肽抑制剂结合SARS-Cov 3CLpro的结合位点，以HIS41和CYS145作为对接活性口袋，据此展开基于结构的药物筛选。 最终，根据37800个化合物的对接分进行排序，筛选出了前五名化合物：芦丁、山柰酚、木犀草素、槲皮素和长春花碱，如图1所示。
实施例2，山柰酚抗病毒实验。实验设计如表1所示，无菌96孔培养板,每孔加入100μL浓度为2×105 cells/mL VeroE6细胞，37℃、5% CO2培养箱培养24小时；培养板实验组和病毒对照组加入100 TCID50病毒液100 μL/孔，37℃、5% CO2培养箱吸附2小时；2小时后，弃去96孔培养板中细胞培养液；山柰酚稀释成125μM、62.5μM和31.25μM三个不同浓度，每个浓度3个复孔，100μL/孔加入上述药液；细胞37℃、5% C02孵箱孵育3-4天；光学显微镜下观察细胞病变（CPE），细胞出现病变程度按以下6级标准记录：“-”无病变出现；“±”为细胞病变少于10%；“+”为细胞病变约25%；“+ +”为细胞病变约50%；“+ + +”为约75%的细胞出现病变：“+ + + +”为75%以上病变。采用Reed-Muench法或GraphPad Prism5.0计算半数有效浓度(IC50)。判断药效标准：具有50%的抑制病毒CPE的浓度视为有效浓度。以上实验操作均在BSL-3实验室内完成。
表1 实验分组及药物浓度
| 分组 | 药物 | 药物浓度（μM） |
| 实验组 | 山柰酚 | 125、62.5、31.25 |
| 病毒对照组 | COVID-19病毒液 | 100 TCID50/孔 |
| 细胞对照 | 培养基 |
通过观察细胞病变（CPE）并记录实验结果，采用Reed-Muench法或GraphPad Prism5.0计算半数有效浓度(IC50)，实验结果如表2和图2所示。
表2 山柰酚抗新型冠状病毒药效结果
| 药物浓度（μM） | 抑制率（%） |
| 125.00 | 88.33±12.58 |
| 62.50 | 93.33±5.77 |
| 31.25 | 40.00±34.64 |
从表2和图2的实验结果可以看出山柰酚在62.50-125.00µg/ml的浓度范围内对新型冠状病毒感染Vero E6细胞致细胞病变具有显著的抑制作用。
Claims (4)
1.基于分子模拟发现山柰酚在COVID-19病毒中的新用途。
2.根据权利要求1所述的基于分子模拟发现山柰酚在COVID-19病毒中的新用途，其特征在于，虚拟筛选以COVID-19的3CL主蛋白酶为靶标蛋白，HIS41和CYS145为对接活性口袋。
3.根据权利要求1所述的基于分子模拟发现山柰酚在COVID-19病毒中的新用途，其特征在于，化合物山柰酚从中药小分子TCM数据库中虚拟筛选而出。
4.根据权利要求1所述的基于分子模拟发现山柰酚在COVID-19病毒中的新用途，其特征在于，山柰酚在62.50-125.00µg/ml的浓度范围内对新型冠状病毒感染Vero E6细胞致细胞病变具有显著的抑制作用。
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| CN112063708A (zh) * | 2020-09-11 | 2020-12-11 | 成都中医药大学 | 一种从中药中筛选药物活性化合物的方法及作用剂 |
| CN112168899A (zh) * | 2020-09-30 | 2021-01-05 | 上海中医药大学 | 抑制冠状病毒3cl蛋白水解酶的藤茶提取物及其用途 |
| CN112525804A (zh) * | 2020-11-21 | 2021-03-19 | 烟台智医医药科技有限公司 | 全血细胞计数在预测SARS-CoV-2感染中的应用 |
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| CN112063708A (zh) * | 2020-09-11 | 2020-12-11 | 成都中医药大学 | 一种从中药中筛选药物活性化合物的方法及作用剂 |
| CN112168899A (zh) * | 2020-09-30 | 2021-01-05 | 上海中医药大学 | 抑制冠状病毒3cl蛋白水解酶的藤茶提取物及其用途 |
| CN112168899B (zh) * | 2020-09-30 | 2022-07-01 | 上海中医药大学 | 抑制冠状病毒3cl蛋白水解酶的藤茶提取物及其用途 |
| CN112525804A (zh) * | 2020-11-21 | 2021-03-19 | 烟台智医医药科技有限公司 | 全血细胞计数在预测SARS-CoV-2感染中的应用 |
| CN113230288A (zh) * | 2021-06-29 | 2021-08-10 | 安徽省森湶谷药业股份有限公司 | 百蕊草或百蕊草提取物或百蕊草萃取物作为新型冠状病毒治疗药物或抗病毒制剂用途 |
| CN113230289A (zh) * | 2021-07-01 | 2021-08-10 | 安徽省森湶谷药业股份有限公司 | 桑黄和百蕊草复方作为新型冠状病毒治疗药物或抗病毒制剂的用途 |
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