瑞德西韦及其合成中间体结构和性质的计算分析  

Theoretical study on the structure and properties of Remdesivir and its synthetic intermediates

作　　者：陈蒙仪 孙祥 黄罗仪 王朝杰 CHEN Mengyi;SUN Xiang;HUANG Luoyi;WANG Chaojie(Department of Pharmacy,the First Affiliated Hospital of Wenzhou Medical University,Wenzhou 325015,China;School of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou 325035,China)

机构地区：[1]温州医科大学附属第一医院药学部,浙江温州325015 [2]温州医科大学药学院,浙江温州325035

出　　处：《温州医科大学学报》2021年第9期689-698,共10页Journal of Wenzhou Medical University

基　　金：国家自然科学基金资助项目(21177098);浙江省自然科学基金资助项目(LY16B070006)。

摘　　要：目的:研究具广谱抗病毒活性的潜在治疗新型冠状病毒肺炎(COVID-19)的瑞德西韦及其合成中间体结构与性质之间的关系。方法:采用密度泛函理论方法X3LYP/6-311+G(2d,p)对瑞德西韦及其合成中间体13种化合物的分子结构、反应活性位点(分子表面静电势、原子电荷、前线分子轨道)和红外光谱进行分析,并运用概念密度泛函理论重点对化合物5和瑞德西韦(6a)的反应活性指数(化学势、化学硬度、亲电指数、亲核力差值指数和亲电力差值指数)差异比较,再利用药代动力学平台开展成药性评价。结果:几何结构分析化合物6a和12b,理论计算值和实验值基本吻合。分子静电势和原子电荷分析结果均表明,瑞德西韦及其中间体结构上的羟基氧易发生亲电反应,氨基氢和羟基氢易发生亲核反应。前线分子轨道分布说明鸟嘌呤类似物结构是瑞德西韦的活性母核结构,化合物5的活性优于瑞德西韦(6a)。药代动力学预测化合物2、9、12a和12b的成药性较好,并推测瑞德西韦(6a)可能对COVID-19疗效甚微或基本无效。结论:化合物5具有潜在研究价值,瑞德西韦疗效有待进一步探索。Objective:To make theoretical calculation of the relationship between the structure and properties of Remdesivir and its synthetic intermediates as a potential treatment of COVID-19 pneumonia with broad spectrum antiviral activity.Methods:The molecular structures,reactive sites(surface electrostatic potential,atomic charge,frontier molecular orbital)and infrared spectra of 13 compounds of Remdesivir and its synthetic intermediates were computed at the level of X3LYP/6-311+G(2d,p)in density functional theory,and using the conceptual density functional theory to analyze the reactivity indices(chemical potentials,chemical hardness,electrophilic index,nuclophilicity and electrophilicity difference indices)of compound 5 and Remdesivir(6a),and then pharmaceutical evaluation was made by using pharmacokinetic platform.Results:The geometric structure parameters of compounds 6a and 12b showed the theoretical and experimental values were in good agreement with each other.The molecular electrostatic potential and the atomic charge analysis indicated that hydroxyl oxygen on the structure of Remdesivir and its intermediate were prone to electrophilic reagent,and nucleophilic activity near amino hydrogen and hydroxyl hydrogen was higher.The distribution of frontier molecular orbitals indicated that the guanine analogue structure is the active core structure of Remdesivir,and the activity of compound 5 was better than Remdesivir(6a).According to the pharmacokinetic prediction,compounds 2,9,12a and 12b showed good druggability,while Remdesivir(6a)was speculated from ADME/Tox data to have little or no efficacy against COVID-19 pneumonia.Conclusion:Compound 5 has potential research value,and the efficacy of Remdesivir needs to be further explored.

关 键 词：瑞德西韦 中间体 反应活性位点 密度泛函理论 

分 类 号：R445.6[医药卫生—影像医学与核医学]