计算机辅助复方苦参注射液中抑制p21活化激酶1的活性成分预测及分子机制研究  

Computer-aided prediction and molecular mechanism investigation of active components in compound Kushen injection inhibiting p21-activated kinase 1

作　　者：林琳[1,2,3] 常静杰[1] 田耀洲 陈姣 LIN Lin;CHANG Jingjie;TIAN Yaozhou;CHEN Jiao(Affiliated Hospital of Integrated Traditional Chinese and Western Medicine,Nanjing University of Chinese Medicine,Nanjing 210028,P.R.China;Jiangsu Province Academy of Traditional Chinese Medicine,Nanjing 210028,P.R.China;Shenzhen Hospital of Guangzhou University of Chinese Medicine,Shenzhen,Guangdong 518000,P.R.China)

机构地区：[1]南京中医药大学附属中西医结合医院,南京210028 [2]江苏省中医药研究院,南京210028 [3]广州中医药大学深圳医院(福田),广东深圳518000

出　　处：《生物医学工程学杂志》2024年第2期313-320,共8页Journal of Biomedical Engineering

基　　金：国家自然科学基金资助项目(81973527);第七批全国老中医药专家学术经验继承工作项目(国中医药人教函〔2022〕76号)。

摘　　要：靶向p21活化激酶1(PAK1)是胰腺癌治疗的新策略。复方苦参注射液中含有多种抗胰腺癌成分,但具体作用靶点未知。本研究基于分子对接的虚拟筛选发现,复方苦参注射液中的14α-羟基苦参碱与PAK1的别构调节位点具有较高的结合自由能。分子动力学模拟发现,14α-羟基苦参碱使PAK1的α1和α2螺旋向外延伸形成一个较深的别构调节口袋,同时诱导三磷酸腺苷(ATP)结合口袋处的β-折叠向内关闭,导致ATP结合口袋处于“半闭合”状态而失活。当去除14α-羟基苦参碱后,PAK1从失活构象向活性构象转变,因此推测,14α-羟基苦参碱可能是PAK1的可逆别构调节抑制剂。本研究采用现代技术方法对中药活性成分进行研究,为天然产物的开发利用及寻找新的胰腺癌治疗方案奠定基础。Targeting p21-activated kinase 1(PAK1)is a novel strategy for pancreatic cancer treatment.Compound Kushen injection contains many anti-pancreatic cancer components,but the specific targets are unknown.In this study,14α-hydroxymatrine,an active component of Kushen injection,was found to possess high binding free energy with the allosteric site of PAK1 by molecular docking based virtual screening.Molecular dynamics simulations suggested that 14α-hydroxymatrine caused the α1 and α2 helices of the allosteric site of PAK1 to extend outward to form a deep allosteric regulatory pocket.Meanwhile,14α-hydroxymatrine induced the β-folding region at the adenosine triphosphate(ATP)-binding pocket of PAK1 to close inward,resulting in the ATP-binding pocket in a“semi-closed”state which caused the inactivation of PAK1.After removal of 14α-hydroxymatrine,PAK1 showed a tendency to change from the inactive conformation to the active conformation.We supposed that 14α-hydroxymatrine of compound Kushen injection might be a reversible allosteric inhibitor of PAK1.This study used modern technologies and methods to study the active components of traditional Chinese medicine,which laid a foundation for the development and utilization of natural products and the search for new treatments for pancreatic cancer.

关 键 词：复方苦参注射液 p21活化激酶1 14α-羟基苦参碱 胰腺癌 分子对接 分子动力学模拟 

分 类 号：R735.9[医药卫生—肿瘤]