海洋真菌来源丁内酯I的单胺氧化酶抑制活性及结构类似物虚拟筛选  

Monoamine Oxidase Inhibition of Butyrolactone I from Marine Aspergillus terreus and Virtual Screening of Its Analogs

作　　者：杨煜 周龙建 刘亚月 王远 张翼 YANG Yu;ZHOU Longjian;LIU Yayue;WANG Yuan;ZHANG Yi(College of Food Science and Technology,Guangdong Ocean University/Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety/Guangdong Provincial Engineering Laboratory for Marine Biological Products/Guangdong Provincial Engineering Technology Research Center of Seafood/Key Laboratory of Advanced Processing of Aquatic Product of Guangdong Higher Education Institution/Guangdong Provincial Center for Modern Agricultural Scientific Innovation/Marine Biomedicine Research and Development Center at Shenzhen Institute of Guangdong Ocean University/Zhanjiang Municipal Key Laboratory of Marine Drugs and Nutrition for Brain Health/Research Institute for Marine Drugs and Nutrition,Guangdong Ocean University,Zhanjiang 524088,China;Southern Marine Science and Engineering Guangdong Laboratory(Zhanjiang),Zhanjiang 524088,China;Collaborative Innovation Center of Seafood Deep Processing,Dalian Polytechnic University,Dalian 116034,China)

机构地区：[1]广东海洋大学食品科技学院/广东省水产品加工与安全重点实验室/广东省海洋生物制品工程实验室/广东省海洋食品工程技术研究中心/水产品深加工广东普通高等学校重点实验室/广东省现代农业科技创新中心/广东海洋大学深圳研究院海洋医药研发中心/湛江市脑健康海洋药物与营养品重点实验室/广东海洋大学海洋药物研究所,广东湛江524088 [2]南方海洋科学与工程广东省实验室(湛江),广东湛江524006 [3]海洋食品精深加工关键技术省部共建协同创新中心/大连工业大学,辽宁大连116034

出　　处：《广东海洋大学学报》2023年第6期119-128,共10页Journal of Guangdong Ocean University

基　　金：广东省基础与应用基础研究基金自然科学基金(面上项目)(2022A1515010783);广东省科技专项资金-基础与应用基础研究专题(2021A05240);国家自然科学基金(21807015);广东省普通高校重点领域专项(生物医药与健康)(2021ZDZX2064);深圳市科创委基础研究面上项目(JCYJ20220530162014032,JCYJ20190813105005619);湛江市海洋青年人才创新项目(2022E05010)。

摘　　要：【目的】为研究海洋土曲霉(Aspergillus terreus)C23-3的次级代谢产物中的单胺氧化酶抑制剂及其抑制作用类型,借助计算机模拟方法探讨同类型化合物对单胺氧化酶的潜在抑制活性及构效关系,以开发单胺氧化酶抑制剂。【方法】采用活性引导下的色谱方法分离纯化得到活性化合物,采用核磁共振、质谱、圆二色谱分析鉴定其结构,采用酶标比色法评价化合物对单胺氧化酶抑制作用。使用Autodock vina对其结构类似物进行抑制单胺氧化酶活性虚拟筛选。【结果】1)分离鉴定得到一个具有单胺氧化酶抑制活性的化合物丁内酯I;2)丁内酯I对单胺氧化酶A和单胺氧化酶B的抑制作用为可逆非竞争性抑制,对单胺氧化酶A的半抑制浓度(IC50)为21.45μmol/L,抑制常数Ki=6.27μmol/L;对单胺氧化酶B的IC50为24.16μmol/L,Ki=12.61μmol/L;3)分子对接显示丁内酯I可与单胺氧化酶形成多个氢键,五元内酯环为α,γ‒二芳基取代、含有苯并吡喃或苯并呋喃基团的aspvinone类丁内酯化合物在虚拟筛选中对单胺氧化酶最小结合亲和力得分更低(即结合力更强)。【结论】丁内酯I是可逆的单胺氧化酶抑制剂,对单胺氧化酶的抑制为非竞争性抑制。真菌来源丁内酯类化合物可作为单胺氧化酶抑制剂的新来源。【Objective】This study aimed to investigate the monoamine oxidase(MAO)inhibitors from the secondary metabolites of marine Aspergillus terreus C23-3 and their inhibitory types,and investigate the potential MAO inhibitory activity and structure-activity relationship of butyrolactone analogs by computer simulation to develop MAO inhibitors.【Method】The bioactive compound was obtained by bioactivity-guided chromatographic separation.Its structure was identified by nuclear magnetic resonance spectrometry,mass spectrometry and circular dichroism analyses.The inhibition of the compounds on monoamine oxidase was assayed by colorimetric method in microtiter plates.Autodock vina was used to evaluate the butyrolactone I analogs for monoamine oxidase inhibitory potentials.【Result】1)An active compound,butyrolactone I,was isolated and identified.2)The inhibitory effect of butyrolactone I on monoamine oxidases A and B was reversible and noncompetitive,the semi-inhibition concentrations(IC50)were 21.45μmol/L and 24.16μmol/L respectively,the inhibition constant Ki was 6.27μmol/L and 12.61μmol/L respectively.3)Molecular docking showed that butyrolactone I could form multiple hydrogen bonds with amino acid residues of MAOs.Aspvinone-type butyrolactone analogs,which haveα,γ-biaryl substituted five-member lactone ring and benzopyran or benzofuran groups,scored lower on the minimal binding affinity with monoamine oxidases in virtual screening.【Conclusion】Butyrolactone I is a reversible inhibitor of monoamine oxidase,and its inhibition to monoamine oxidase is noncompetitive.Fungal butyrolactones are new source of MAO inhibitors.

关 键 词：海洋真菌 次级代谢产物 单胺氧化酶 抑制类型 虚拟筛选 

分 类 号：O629.6[理学—有机化学]