CN111840561B - S100a9抑制剂在制备治疗胰腺炎的药物中的应用 - Google Patents
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Abstract
本发明公开了S100A9抑制剂在制备治疗胰腺炎的药物中的应用，属于生物医学技术领域。一种S100A9抑制剂在制备治疗胰腺炎的药物中的应用，所述S100A9抑制剂如Chemdiv ID：0884‑0014或3948‑1191或3232‑0780所示。本发明采用S100A9抑制剂预处理胰腺炎体外模型，证明了S100A9抑制剂(ID:0884‑0014,3948‑1191,3232‑0780)可提高HPDE6‑C7细胞活力，减少STC诱导的细胞损伤。本发明为利用S100A9抑制剂作为治疗胰腺炎的一种新型药物提供了依据。
Description
技术领域
本发明涉及S100A9抑制剂在制备治疗胰腺炎的药物中的应用，属于生物医学技术领域。
背景技术
急性胰腺炎是一种临床常见的胰腺局部炎症，以胰腺局部坏死和多器官功能障碍(Multiple organ dysfunction syndrome,MODS)为主要特征的消化系统疾病，死亡率高居各急腹症之首。目前急性胰腺炎已形成以早期支持治疗为主的非手术治疗体系，但由于对该疾病发病机制的认识不足，迄今还没有特效的防治药物。针对胰腺炎患者的临床观察发现，胰管最容易受到胆石症和和内镜逆行胰管造影术的伤害性刺激，胰导管是最容易暴露于胰腺炎常见伤害性刺激的组织。因此，充分研究胰腺炎导管损伤后的病理生理变化以期寻求更好的药物治疗手段已经显得刻不容缓。
S100A9是钙结合蛋白S100蛋白家族的成员,主要在髓系起源的早期分化细胞表达。研究发现，S100A9蛋白通过Ca2+依赖的方式形异源二聚体，通过与效应靶蛋白相互作用，在调节体内钙平衡、细胞凋亡和炎症反应等生理病理过程中发挥生物学作用。但目前鲜有文献报道S100A9与胰腺炎的关系。
发明内容
为解决上述问题，本发明基于药物靶点库(Chemdiv)筛选出评分最高的8种S100A9抑制剂，采用MTT法检测其对人正常胰腺导管上皮细胞株HPDE6-C7的细胞毒性，并采用体外胰腺炎模型筛选出3种可能有效的治疗胰腺炎药物。
本发明提供了一种S100A9抑制剂在制备治疗胰腺炎的药物中的应用，所述S100A9抑制剂如式Ⅰ、式Ⅱ或式Ⅲ所示；
进一步地，上述技术方案中，所述的胰腺炎为急性胰腺炎。
进一步地，上述技术方案中，所述S100A9抑制剂为S100A9-VNN1抑制剂。
一种治疗胰腺炎的药物，包含S100A9抑制剂及其药学上可接受的盐。
本发明通过研究发现S100A9蛋白水平在胰腺炎导管组织中显著上调，S100A9shRNA干扰质粒和基因敲除小鼠能够显著减轻体外、内胰腺炎损伤；且其作用机制涉及S100A9上调VNN1介导的ROS释放水平。因此，抑制S100A9-VNN1相互作用是改善胰腺炎的一种潜在治疗方式。基于此，本发明采用分子对接技术以及胰腺炎体外模型，从药物靶点库(Chemdiv)筛选出了三种治疗胰腺炎的高效S100A9-VNN1抑制剂 (ID:0884-0014,3948-1191,3232-0780)。
发明有益效果
本发明采用S100A9抑制剂预处理胰腺炎体外模型，证明了S100A9抑制剂(ID:0884-0014,3948-1191,3232-0780)可提高HPDE6-C7细胞活力，减少牛磺胆酸钠(STC) 诱导的细胞损伤。本发明为利用S100A9抑制剂作为治疗胰腺炎的一种新型药物提供了依据。
附图说明
图1为S100A9与VNN1的结合模型；(A)S100A9与VNN1的表面相互作用；(B) S100A9与VNN1的三维相互作用。
图2为虚拟筛选的8种S100A9-VNN1相互作用抑制剂。
图3为S100A9抑制剂毒性实验。
图4为S100A9抑制剂药效筛选。
图5为S100A9抑制剂对STC诱导细胞损伤改善情况图。
具体实施方式
下述非限定性实施例可以使本领域的普通技术人员更全面地理解本发明，但不以任何方式限制本发明。
实施例1
一、实验方案：
1.分子对接：S100A9蛋白和VNN1蛋白的3D结构从RCSB蛋白数据库(PDB ID: 5I8N代表S100A9，4CYF代表VNN1)下载。利用ClusPro中的蛋白质-蛋白质对接功能进行分子对接模拟和预测复合物的结合亲和力；利用MOE v2018.01分析对接结构和界面残留物，最终由PyMOL生成分子图形，如图1所示。
2.虚拟筛选：MOE v2015.1001中的Dock模块用于基于受体的虚拟筛选(SBVS)。S100A9蛋白被定义为受体，Chemdiv的10万个化合物被定义为虚拟筛选文库。在 S100A9与VNN1相互作用的残基附近选择受体结合位点，最终选择评分排名前8的抑制剂，8种抑制剂的结构式如图2所示。
3.毒性实验：采用MTT法测定8种S100A9抑制剂对HPDE6-C7细胞(人正常胰腺导管上皮细胞，购自上海钦诚生物科技有限公司，QCB429)的毒性，具体步骤如下：将细胞以1×105个/ml(100μl)的浓度接种于96孔板中，采用含10％胎牛血清的 DMEM培养液，于5％CO2、37℃饱和湿度条件下培养24h后，分别加入不同浓度(终浓度为10,1,0.1,0.01,0.001和0μM)S100A9抑制剂(DMSO溶解，终浓度<0.1％)处理 24h。随后，加入10μl MTT(5mg/ml)37℃避光孵育，4h后吸干MTT，加入100μl DMSO，震荡溶解10min，酶标仪测定吸光度A490。将采集到的数据进行计算，得到不同组别的细胞活力抑制率,筛选出最大的无毒剂量进行后续的药效研究。每个浓度设6个复孔，每组实验重复3次。实验结果如图3所示。
4.药效实验：将HPDE6-C7细胞以1×105个/ml(100μl)的浓度接种于96孔板中，采用含10％胎牛血清的DMEM培养液，于5％CO2、37℃饱和湿度条件下培养24h后，分成10组：1)对照组；2)模型组；3)8组S100A9抑制剂组(化合物1、2、3、4、5、 6、7和8)。S100A9抑制剂组分别加入最大的无毒剂量(1、0.001、0.001、0.001、1、 0.001、0.001和0.001μM)的S100A9抑制剂(DMSO溶解，终浓度<0.1％)；对照组和模型组分别加入同等体积的DMSO(终浓度<0.1％)。24h后，模型组和8组S100A9抑制剂组的细胞加入1015μM牛磺胆酸钠(STC，DMEM溶解)溶液作用1h，对照组不做处理，最后采用MTT法检测细胞活力，筛选可能用于治疗胰腺炎的S100A9抑制剂。每个浓度设6个复孔，每组实验重复3次，实验结果如图4所示。并采用倒置显微镜镜下观察细胞损伤情况并进行拍照，实验结果如图5所示。
二、实验结果：
1.分子对接：S100A9和VNN1的相互结合模型如图1所示。橙色结构代表 S100A9，绿色结构代表VNN1；红色虚线代表氢键，蓝色虚线代表盐桥。对接模拟研究表明，VNN1中的残基His228、Arg259、Ser309、His310、Ser311、Val313、Val314、 Asn315、Ser321、Ile323、Glu324、Phe431和Gln434与S100A9中的残基Glu52、Lys57、 Arg85、Glu92、Met94、Gly100、Gly102、His103和His105通过盐桥和氢键相互作用结合。具体对接结果见表1。
表1 S100A9与VNN1相互作用氨基酸残基列表
2.虚拟筛选：根据S100A9和VNN1相互结合的氨基酸残基筛选出8种抑制剂，所述8种抑制剂结构式如图2。
3.毒性实验：如图3所示，结果发现这8种抑制剂(ID号为：0683-0021、0884-0014、2372-3991、3948-1149、3948-1191、0249-0003、2324-0140、3232-0780)的最大无毒剂量依次为1、0.001、0.001、0.001、1、0.001、0.001、0.001μM。
4.药效实验：MTT结果显示，同模型组相比，3种S100A9抑制剂(ID:0884-0014,3948-1191,3232-0780)能够显著提高HPDE6-C7细胞活力(图4)，同时，倒置显微镜明场观察到这3种抑制剂能够改善细胞损伤，减少细胞碎片(图5)。
Claims (2)
1.一种S100A9抑制剂在制备治疗胰腺炎的药物中的应用，其特征在于，所述S100A9抑制剂如式Ⅰ、式Ⅱ或式Ⅲ所示；
2.根据权利要求1所述的应用，其特征在于，所述的胰腺炎为急性胰腺炎。
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