CN111700895A - 血管紧张素转化酶抑制剂及其筛选方法和应用 - Google Patents
血管紧张素转化酶抑制剂及其筛选方法和应用 Download PDFInfo
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Abstract
本发明涉及血管紧张素转化酶抑制剂及其筛选方法和应用，所述血管紧张素转化酶抑制剂包括来自药食两用植物中的熊果酸和/或甘草次酸。本发明首次从诺丽果和甘草中分别筛选出两种对血管紧张素转化酶具有显著抑制活性的物质，分别是熊果酸和甘草次酸，其中，熊果酸对血管紧张素转化酶抑制活性的IC50值为100.78±0.36μM，甘草次酸对血管紧张素转化酶抑制活性的IC50值为182.75±0.12μM，提高了诺丽果和甘草这两种植物作为食药两用植物的利用价值。
Description
技术领域
本发明属于生物医药技术领域，具体涉及血管紧张素转化酶抑制剂及其筛选方法和应用。
背景技术
高血压是最常见的慢性疾病之一，也是心血管和脑血管疾病的重要危险因素，此外，高血压是世界上死亡率较高的疾病之一，这就引起了人们的高度关注，因此研究关于降低高血压的药品、保健食品以及抑制机理就变得至关重要。血管紧张素转化酶(ACE)作为肾素-血管紧张素系统(RAS)和Kraftwerk-Kennzeichen系统(KKS)的关键调节剂，在血压和体液稳态中起着重要的生理作用。ACE可以导致血管紧张素II的产生和缓激肽的降解，因此，抑制ACE被认为是预防和治疗高血压及相关疾病的有效方法。
合成类的ACE抑制剂(例如卡托普利、依那普利和普萘拉普利)通常具有致人低血压、干咳和肾功能受损等副作用，因此，寻找鉴定天然类的ACE抑制剂比化学合成的ACE抑制剂更可取。
CN103550403A公开了一种从茶果皮中提取血管紧张素转化酶抑制剂的方法，该方法包括以下步骤：向干燥后粉碎的茶果皮中加入丙酮，浸泡后离心得到茶果皮，向得到的茶果皮中加入缓冲液超声提取，再离心得到提取液，向提取液中加入氯仿，萃取得到萃余液，萃余液浓缩后冷冻干燥得到初提取物，然后将初提取物加入到乙醇水溶液中，离心得到上清液，最后上清液浓缩后冷冻干燥，即得到血管紧张素转化酶抑制剂。
CN105131083A公开了两种具有血管紧张素转化酶抑制活性的扁杏仁肽及其制备方法，其中一种扁杏仁肽的氨基酸序列为Met-His-Thr-Asp-Asp，另一种扁杏仁肽的氨基酸序列为Gln-His-Thr-Asp-Asp。这两种扁杏仁肽是以扁杏仁为原料，先提取扁杏仁蛋白，将扁杏仁蛋白酶解得到扁杏仁总肽，再经葡聚糖凝胶层析、反相制备色谱分离得到。实验结果表明，这两种扁杏仁肽具有较高的血管紧张素转化酶抑制活性，前者对血管紧张素转化酶抑制活性的IC50值为67.52±0.05μg/mL，后者对血管紧张素转化酶抑制活性的IC50值为43.18±0.07μg/mL，且细胞毒性较低。
但是，现有技术中对于天然类的ACE抑制剂的类型报道还非常有限，因此，开发新型的天然类ACE抑制剂是非常有意义的。
诺丽果作为药用和食用植物，具有广泛的生物活性，其所含的主要化学成分是蒽醌、环烯醚酮、木质素化合物、糖苷、熊果酸和其他化合物。甘草也是一种具有多种生理功能的药草和食用植物，现代医学研究表明，甘草可以保护肝脏，抵抗炎症，抵抗病菌，抵抗癌症并增强免疫力。
发明内容
针对现有技术的不足，本发明的目的在于提供血管紧张素转化酶抑制剂及其筛选方法和应用。
为达到此发明目的，本发明采用以下技术方案：
一方面，本发明提供血管紧张素转化酶抑制剂，所述血管紧张素转化酶抑制剂包括来自药食两用植物中的熊果酸和/或甘草次酸。
本发明首次从诺丽果和甘草中分别筛选出两种对血管紧张素转化酶具有显著抑制活性的物质，分别是熊果酸和甘草次酸，其中，熊果酸是存在于天然植物中的一种五环三萜类化合物，现有研究报道其具有镇静、抗炎、抗菌、抗糖尿病、抗溃疡、降低血糖等多种生物学效应，熊果酸还具有明显的抗氧化功能，因而被广泛地用作医药和化妆品原料。甘草次酸是常见的药食两用食品，甘草的甜味来自甘草酸和甘草次酸，前者是一类三萜类皂苷，约占甘草根干重的4％-5％，甜度为蔗糖的50倍，甘草次酸是由甘草酸水解脱去糖酸链而形成，甜度为蔗糖的250倍，现有研究报道甘草次酸具有肾上腺皮质激素样作用、抗炎及抗免疫作用、镇咳祛痰作用、抗肿瘤作用等。本发明成功拓展了熊果酸和甘草次酸的可应用领域，其可以作为血管紧张素转化酶抑制剂应用于降血压药物或食物中。
优选地，所述血管紧张素转化酶抑制剂还包括药用辅料。
优选地，所述药用辅料包括稀释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、乳化剂、助溶剂、增溶剂、渗透压调节剂、表面活性剂、pH调节剂、抗氧剂、抑菌剂或缓冲剂中的任意一种或至少两种的组合。所述至少两种的组合例如稀释剂和赋形剂的组合、乳化剂和助溶剂的组合、填充剂和粘合剂和润湿剂的组合等。
优选地，所述血管紧张素转化酶抑制剂的剂型包括片剂、散剂、混悬剂、颗粒剂、胶囊剂、注射剂、喷雾剂、溶液剂、灌肠剂、乳剂、膜剂、栓剂、贴剂、滴鼻剂或滴丸剂。
本发明所述熊果酸和/或甘草次酸可单独给药也可以与辅料搭配做成适当的剂型进行给药，当剂型为片剂时，可包含有赋形剂，例如微晶纤维素、淀粉或碳酸钙等；也可以包含崩解剂，例如交联羧甲基纤维素钠等。当剂型为胶囊剂时，其可制备成为硬胶囊或软胶囊，熊果酸和/或甘草次酸及辅料可以制备成为粉末状或颗粒状填充进入胶囊中。当剂型为混悬剂时，可加入矫味剂、助悬剂等调节口味与口感。当剂型为乳剂时，可适当添加乳化剂、助溶剂来调节溶解度、乳化度进行给药。
优选地，所述药物的给药途径包括静脉注射、腹腔注射、肌肉注射、皮下注射、口服给药、舌下给药、鼻腔给药或经皮给药。
一般以片剂或胶囊剂的方式进行口服给药，另外，以片剂或胶囊剂进行口服给药时，可以制备成控释制剂或缓释制剂，根据需要的药效及作用时间，选择合适剂量的控释辅料或缓释辅料。
在本发明中，所述熊果酸对血管紧张素转化酶抑制活性的IC50值为100.78±0.36μM。
在本发明中，所述甘草次酸对血管紧张素转化酶抑制活性的IC50值为182.75±0.12μM。
另一方面，本发明提供一种如上所述的血管紧张素转化酶抑制剂的筛选方法，所述筛选方法包括：
使用分子对接软件对诺丽果和/或甘草中的活性物质进行分子对接，对分子对接结果进行筛选；然后对筛选出的活性物质进行IC50值测定，进一步筛选出IC50值最低的活性物质，即为所述血管紧张素转化酶抑制剂。
具体地，通过查阅文献资料，筛选出诺丽果和/或甘草中含量相对较高的若干种活性物质，使用分子对接软件例如DS软件对诺丽果和/或甘草中的上述活性物质进行分子对接试验，筛选出分子对接结果相对更好的若干种候选活性物质；然后对筛选出的活性物质进行IC50值测定，进一步筛选出抑制效果最优的活性物质，即为所述血管紧张素转化酶抑制剂。
再一方面，本发明提供一种降血压食物，所述降血压食物包括如上所述的血管紧张素转化酶抑制剂。
再一方面，本发明提供一种降血压药物，所述降血压药物包括如上所述的血管紧张素转化酶抑制剂。
优选地，所述降血压药物还包括药用辅料。
优选地，所述药用辅料包括稀释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、乳化剂、助溶剂、增溶剂、渗透压调节剂、表面活性剂、pH调节剂、抗氧剂、抑菌剂或缓冲剂中的任意一种或至少两种的组合。所述至少两种的组合例如稀释剂和赋形剂的组合、乳化剂和助溶剂的组合、填充剂和粘合剂和润湿剂的组合等。
优选地，所述降血压药物的剂型包括片剂、散剂、混悬剂、颗粒剂、胶囊剂、注射剂、喷雾剂、溶液剂、灌肠剂、乳剂、膜剂、栓剂、贴剂、滴鼻剂或滴丸剂。
相对于现有技术，本发明具有以下有益效果：
本发明首次从诺丽果和甘草中分别筛选出两种对血管紧张素转化酶具有显著抑制活性的物质，分别是熊果酸和甘草次酸，其中，熊果酸对血管紧张素转化酶抑制活性的IC50值为100.78±0.36μM，甘草次酸对血管紧张素转化酶抑制活性的IC50值为182.75±0.12μM。通过ADMET属性分析得到甘草次酸和熊果酸均具有中等吸收，且都是无肝毒性的，不是CYP2D6抑制剂，提高了诺丽果和甘草这两种植物作为食药两用植物的利用价值。
附图说明
图1是甘草次酸和熊果酸的ADMET属性分析图；
图2是甘草次酸与血管紧张素转化酶之间的3D空间相互作用示意图；
图3是甘草次酸与血管紧张素转化酶之间的相互作用二维平面图；
图4是熊果酸与血管紧张素转化酶之间的3D空间相互作用示意图；
图5是熊果酸与血管紧张素转化酶之间的相互作用二维平面图。
具体实施方式
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了，所述实施例仅仅是帮助理解本发明，不应视为对本发明的具体限制。
实施例1
本实施例从诺丽果和甘草中筛选并鉴定出两种对血管紧张素转化酶具有显著抑制作用的物质熊果酸和甘草次酸，包括如下步骤：
(1)整理出诺丽果和甘草中含量相对较高的几种活性成分，分别是：诺丽果中的熊果酸、茜草素、棕榈酸和莨菪亭，甘草中的甘草次酸、槲皮素、芦丁和β-谷甾醇，作为候选物质；
(2)使用DS软件(全称为Discovery Studio 2017R2 Client)将上述活性物质与血管紧张素转化酶进行分子对接，结果如表1所示：
表1
| 活性物质 | 能量值 | 静电能 | 范德华力 | 势能 |
| 熊果酸 | -111.718 | -27.759 | -9.102 | 70.839 |
| 甘草次酸 | -70.383 | -22.759 | -8.650 | 68.989 |
| 茛菪亭 | 27.428 | -18.695 | 2.302 | -12.083 |
| 槲皮素 | 38.948 | -9.395 | 0.714 | 0.801 |
| 芦丁 | 17.504 | -26.449 | -11.535 | 32.884 |
| 茜草素 | 32.745 | -14.815 | 4.136 | -8.137 |
| β-谷甾醇 | -30.108 | -15.528 | -15.539 | 57.372 |
| 棕榈酸 | 44.058 | -8.778 | -8.051 | -15.268 |
由表1数据可知：由能量值对对接结果进行评定得到熊果酸和甘草次酸的对接结果最好。
(3)对熊果酸和甘草次酸对血管紧张素转化酶抑制活性的IC50值进行计算，方法原理为：血管紧张素转化酶催化马尿酸-1-组氨酸-L-亮氨酸(HHL)释放马尿酸，具体操作为：采用高效液相色谱法对马尿酸的含量进行测定，进而对熊果酸和甘草次酸的ACE抑制活性进行测定。取马尿酰-组胺酰-亮氨酸(HHL)底物溶液，加入熊果酸溶液或甘草次酸溶液混合均匀，在37℃恒温水浴中预热5min，然后加入ACE液充分混合，37℃保温30min后，再加入的1mol/L的HCl溶液终止反应，得到反应液。同时用硼酸缓冲液替代抑制剂溶液作为空白对照组。该反应液直接用HPLC系统进行分析。色谱条件：柱温25℃，流速0.5mL/min，流动相为乙腈:水＝25:75等度洗脱，检测波长228nm。
结果为：熊果酸对血管紧张素转化酶抑制活性的IC50值为100.78±0.36μM，甘草次酸对血管紧张素转化酶抑制活性的IC50值为182.75±0.12μM。
(4)使用DS软件对熊果酸和甘草次酸进行ADMET属性分析，结果如表2所示：
表2
其中：a代表熊果酸和甘草次酸不是CYP2D6的抑制剂；b代表熊果酸和甘草次酸没有毒性，说明二者对人体无害，可以用作ACE的抑制剂；d代表熊果酸和甘草次酸的含量很低，可能具有溶解度，说明二者可以在人体内溶解，就可以作为ACE的抑制剂；e代表熊果酸和甘草次酸具有中等吸收，说明可以被人体较好的吸收，可以用作ACE抑制剂。
甘草次酸和熊果酸的ADMET属性分析图如图1所示，由图1可知：甘草次酸和熊果酸均落入人体肠道吸收模型的99％椭圆置信度内；甘草次酸和熊果酸都落在血脑渗透模型的99％椭圆置信度之外。这说明甘草次酸和熊果酸在人体内的吸收还是不错的，可用做ACE的抑制剂。
(5)使用DS软件分别分析熊果酸和甘草次酸与血管紧张素转化酶之间的相互作用方式，甘草次酸与血管紧张素转化酶之间的3D空间相互作用如图2所示，由图2可知：甘草次酸与ACE的最佳对接姿势；甘草次酸与血管紧张素转化酶之间的二维平面图如图3所示，由图3可知：甘草次酸中的Val380残基、Phe527残基、Try523残基、His353残基、His383残基、His387残基、His513残基与ACE产生相互作用，另外甘草次酸的氧原子与ACE的ZN701形成金属-受体相互作用。
熊果酸与血管紧张素转化酶之间的3D空间相互作用如图4所示，由图4可知：熊果酸与ACE的最佳对接姿势；熊果酸与血管紧张素转化酶之间的二维平面图如图5所示，由图5可知：熊果酸中的Phe512残基、His513残基、His353残基、His387残基、Tyr523残基、His383残基、Val380残基、Val518残基、Ala354残基与ACE发生相互作用。
申请人声明，本发明通过上述实施例来说明本发明的血管紧张素转化酶抑制剂及其筛选方法和应用，但本发明并不局限于上述实施例，即不意味着本发明必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了，对本发明的任何改进，对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等，均落在本发明的保护范围和公开范围之内。
以上详细描述了本发明的优选实施方式，但是，本发明并不限于上述实施方式中的具体细节，在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单变型，这些简单变型均属于本发明的保护范围。
另外需要说明的是，在上述具体实施方式中所描述的各个具体技术特征，在不矛盾的情况下，可以通过任何合适的方式进行组合，为了避免不必要的重复，本发明对各种可能的组合方式不再另行说明。
Claims (10)
1.血管紧张素转化酶抑制剂，其特征在于，所述血管紧张素转化酶抑制剂包括来自药食两用植物中的熊果酸和/或甘草次酸。
2.如权利要求1所述的血管紧张素转化酶抑制剂，其特征在于，所述血管紧张素转化酶抑制剂还包括药用辅料；
优选地，所述药用辅料包括稀释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、乳化剂、助溶剂、增溶剂、渗透压调节剂、表面活性剂、pH调节剂、抗氧剂、抑菌剂或缓冲剂中的任意一种或至少两种的组合。
3.如权利要求1或2所述的血管紧张素转化酶抑制剂，其特征在于，所述血管紧张素转化酶抑制剂的剂型包括片剂、散剂、混悬剂、颗粒剂、胶囊剂、注射剂、喷雾剂、溶液剂、灌肠剂、乳剂、膜剂、栓剂、贴剂、滴鼻剂或滴丸剂。
4.如权利要求1-3中任一项所述的血管紧张素转化酶抑制剂，其特征在于，所述熊果酸对血管紧张素转化酶抑制活性的IC50值为100.78±0.36μM。
5.如权利要求1-4中任一项所述的血管紧张素转化酶抑制剂，其特征在于，所述甘草次酸对血管紧张素转化酶抑制活性的IC50值为182.75±0.12μM。
6.如权利要求1-5中任一项所述的血管紧张素转化酶抑制剂的筛选方法，其特征在于，所述筛选方法包括：
使用分子对接软件对诺丽果和/或甘草中的活性物质进行分子对接，对分子对接结果进行筛选；然后对筛选出的活性物质进行IC50值测定，进一步筛选出IC50值最低的活性物质，即为所述血管紧张素转化酶抑制剂。
7.一种降血压食物，其特征在于，所述降血压食物包括如权利要求1-5中任一项所述的血管紧张素转化酶抑制剂。
8.一种降血压药物，其特征在于，所述降血压药物包括如权利要求1-5中任一项所述的血管紧张素转化酶抑制剂。
9.如权利要求8所述的降血压药物，其特征在于，所述降血压药物还包括药用辅料；
优选地，所述药用辅料包括稀释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、乳化剂、助溶剂、增溶剂、渗透压调节剂、表面活性剂、pH调节剂、抗氧剂、抑菌剂或缓冲剂中的任意一种或至少两种的组合。
10.如权利要求8或9所述的降血压药物，其特征在于，所述降血压药物的剂型包括片剂、散剂、混悬剂、颗粒剂、胶囊剂、注射剂、喷雾剂、溶液剂、灌肠剂、乳剂、膜剂、栓剂、贴剂、滴鼻剂或滴丸剂。
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