摘要
目的研究卡泊芬净引起转氨酶升高的分子作用机制。方法借助STITCH数据库、Drug Bank数据库及在线的Swiss Target Prediction搜集卡泊芬净的基因靶点;利用DisGeNET数据库筛选转氨酶升高的基因靶点;用Origin2019软件绘制韦恩图,找到卡泊芬净导致肝功能损伤的潜在基因靶点;通过DAVID数据库的通路分析,确定对接的基因靶点;以酮康唑化学结构为参比,运用Auto Dock vina分别对卡泊芬净、酮康唑对接;使用Chimera对卡泊芬净与基因靶点的对接结果进行分析和展示。结果14个潜在基因靶点为卡泊芬净导致转氨酶升高的靶点。通路分析后,确定MMP9,STAT3和CASP8为对接的基因靶点。卡泊芬净和酮康唑均与对接基因靶点有较稳定的结合,但酮康唑的结合能小于卡泊芬净。对接结果分析表明:卡泊芬净与MMP9蛋白D链有3条氢键形成,与STAT3蛋白A链有2条氢键形成,与CASP8蛋白无氢键形成。结论卡泊芬净和酮康唑均可导致转氨酶升高,但卡泊芬净引起转氨酶升高的发生率低于酮康唑;卡泊芬净引起转氨酶升高的作用机制可能是与MMP9、STAT3形成氢键,从而激活MMP9,抑制STAT3转录因子。
OBJECTIVE To investigate the mechanism of action for caspofungin-induced aminotransferases elevation.METHODS Gene targets of caspofungin were extracted from STITCH database,Drug Bank database and Swiss Target Prediction online database.Aminotransferases elevation associated gene targets were obtained from DisGeNET databases.Wayne diagrams were drawn using Origin2019 software to find the potential targets for caspofungin-induced liver injury.The gene targets identified by molecular docking were through pathway analysis by DAVID database.Ketoconazole was used as a reference,caspofungin and ketoconazole were subjected to molecular docking studies for gene targets using Auto Dock Vina software and the molecular docking study outcomes were visualized by Chimera software.RESULTS 14 potential gene targets of caspofungin-induced aminotransferases elevation were identified.Through pathway analysis,MMP9,STAT3 and CASP8 were identified as the target proteins for molecular docking.The molecular docking results showed that caspofungin and ketoconazole were binded well to gene targets,but the binding energy of ketoconazole was less than caspofunging.Analysis of docking results showed that three hydrogen bonds were formed between caspofungin and MMP9 protein D chain,two hydrogen bonds were formed between caspofungin and STAT3 protein A chain,but no hydrogen bond was formed between CASP8 protein and caspofungin.CONCLUSION Both caspofungin and ketoconazole can induce aminotransferases elevation,but the incidence of aminotransferase elevation induced by caspofungin was lower.The mechanism of action for caspofungin-induced aminotransferases elevation may be the formation of hydrogen bonds with MMP9 and STAT3,leading to activation of MMP9 protein and inhibition of STAT3 transcription factor.
作者
吴彬
邓小莹
阙慧卿
李彬
叶珩
WU Bin;DENG Xiaoying;QUE Huiqing;LI Bin;YE Heng(Department of Pharmacy,Guangzhou First People's Hospital,Guangzhou,Guangdong 511458,China;Intensive Care Unit,Guangzhou First People's Hospital,Guangzhou,Guangdong 511458,China;Fujian Provincial Key Laboratory of Medical Testing,Institute of Medical Sciences of Fujian Province,Fuzhou,Fujian 350001,China)
出处
《今日药学》
CAS
2022年第9期669-675,共7页
Pharmacy Today
关键词
卡泊芬净
生物信息学
分子对接
转氨酶
作用机制
caspofungin
bioinformatics
molecular docking
aminotransferases
mechanism
