吡唑类和三唑类氨基甲酸酯作为LPAR 1拮抗剂的3D-QSAR、分子对接和分子动力学模拟研究  

Combined 3D-QSAR,molecular docking and molecular dynamics simulation study on pyrazole-and triazole-derived carbamates as LPAR1 antagonists

作　　者：张艺良 吴晗 李慧 刘振明[4] 王昊[3] 洪伟[1,2] ZHANG Yiliang;WU Han;LI Hui;LIU Zhenming;WANG Hao;HONG Wei(School of Chemistry and Chemical Engineering,North Minzu University,Yinchuan 750021,Ningxia,China;Ningxia Key Laboratory of Solar Chemical Conversion Technology,North Minzu University,Yinchuan 750021,Ningxia,China;School of Pharmacy,Ningxia Medical University,Yinchuan 750004,Ningxia,China;State Key Laboratory of Natural and Biomimetic Drugs,School of Pharmaceutical Sciences,Peking University,Beijing 100191,China)

机构地区：[1]北方民族大学化工学院,宁夏回族自治区银川市750021 [2]宁夏太阳能化学转化技术重点实验室,宁夏回族自治区银川市750021 [3]宁夏医科大学,宁夏回族自治区银川市750004 [4]北京大学药学院,北京市100191

出　　处：《计算机与应用化学》2019年第6期685-696,共12页Computers and Applied Chemistry

基　　金：National Natural Science Foundation of China(81660588,81773582);New Catalytic Process in Clean Energy Production(ZDZX201803);the Key R&D Program of Ningxia(2018BFG02004);the Program for Leading Talents of Ningxia Province(KJT2018004)。

摘　　要：溶血磷脂酸(LPA)是一种重要的信号分子,具有多种生物学功能。据报道,阻断LPA与溶血磷脂酸受1(LPAR 1)的结合可能是治疗特发性肺纤维化(IPF)的潜在途径。以25种具有LPAR1拮抗剂能力的吡唑类和三唑类氨基甲酸酯为基础,建立了三维定量构效关系(3D-QSAR)模型。在比较分子场分析(CoMSIA q2=0.510,r2=0.998,rpred2=0.943)的基础上,得到了一个可靠的模型,该模型由立体场、静电场、疏水场、氢键供体场和氢键受体场组成。等高线图显示了化合物的生物活性与其三维结构之间的关系。在预测和化学合成可能性的基础上,设计了8种新的LPAR1拮抗剂,并通过分子对接和分子动力学模拟,分析了具有最佳预测活性的化合物(化合物D5)的结合方式。使用MM-PBSA计算了其结合自由能,表明化合物D5具有较强的结合能力。目前的研究表明,应用计算机模拟技术发现并验证了新的有效的LPAR1拮抗剂,这为今后的药物设计奠定基础。Lysophosphatidic acid(LPA)is an important signaling molecule and regulates multiple biological actions.It has been reported that the blockage of the binding of LPA to lysophosphatidic acid receptor 1(LPAR1)could be a potential way for the idiopathic pulmonary fibrosis(IPF)therapy.The three-dimensional quantitative structure activity relationship(3D-QSAR)model was established based on twenty-five LPAR1 antagonists with pyrazole and triazole-derived carbamate as the center core.A reliable model was obtained based on the application of the comparative molecular field analyses(CoMSIA q2=0.510,r2=0.998,rpred2=0.943),which is composed of stereoscopic field,electrostatic field,hydrophobic field,hydrogen-bond donor field and hydrogen-bond acceptor field.The contour maps showed the relationships between the biological activities of the compounds and their three-dimensional structures.Based on the prediction and the possibility of chemical synthesis,eight new LPAR1 antagonists were designed,and the binding mode of the compound with the best predicated activity(compound D5)was analyzed by using molecular docking and molecular dynamics simulation.The binding free energy was calculated by using MM-PBSA and Normal Mode,which indicated a strong binding ability of the compound D5.The current study showed by using computer modeling technology,novel effective LPAR1 antagonists could be identified,which will be useful as the leading compound for future drug design.

关 键 词：吡唑和三唑衍生氨基甲酸酯 LPAR1拮抗剂 3D-QSAR 分子对接 分子动力学模拟 

分 类 号：O69[理学—化学]