非前药型第三代头孢菌素结构特征和谱学性质的计算分析  

Computational Analysis of Structural Characteristics and Spectral Properties of the Non-Prodrug-Type Third-Generation Cephalosporins

作　　者：余德观 陈旭雷 翁约约 廖颖艺 王朝杰 YU De-guan;CHEN Xu-lei;WENG Yue-yue;LIAO Ying-yi;WANG Chao-jie(Department of Pharmacy,Wenzhou People's Hospital,Wenzhou 325000,China;Department of Pharmacy,Wenzhou Central Hospital,Wenzhou 325000,China;Department of Pharmacy,Eye Hospital of Wenzhou Medical University,Wenzhou 325003,China;School of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou 325035,China)

机构地区：[1]温州市人民医院药剂科,浙江温州325000 [2]温州市中心医院药剂科,浙江温州325000 [3]温州医科大学附属眼视光医院药剂科,浙江温州325003 [4]温州医科大学药学院,浙江温州325035

出　　处：《光谱学与光谱分析》2023年第10期3211-3222,共12页Spectroscopy and Spectral Analysis

基　　金：国家自然科学基金项目(21177098);温州市基础性医疗卫生科技项目(Y20211014)资助。

摘　　要：头孢菌素类品种繁多,应用广泛,结构间存在一定共同特征,但不同结构间的性质差异仍缺乏系统性的比较研究,随着研究技术的不断发展,光谱技术与量子化学计算相结合的方法已成为探究结构性质和观察药物分子电子结构最有效的方法之一。为系统全面地研究非前药型第三代头孢菌素结构与性质的关系,采用密度泛函理论方法X3LYP/6-311+G(d,p)对其几何结构、红外光谱、紫外光谱、分子静电势、前线分子轨道、反应性描述符等进行对比分析并结合分子对接适当验证。该方法计算几何结构如头孢唑肟(CZX)的理论值和实验值基本吻合,头孢菌素的基本结构(BSC)二面角和键角比较相近,但N、O等原子对键长影响较大。头孢他啶(CZX)和头孢噻肟(CTX)的理论计算红外光谱与实验相符,非前药型第三代头孢菌素羰基的C O伸缩振动产生的图谱主要集中在1766~1644 cm^(-1)之间,1650~1550 cm^(-1)范围内产生的强峰主要是N—H面内弯曲振动引起,伯胺会在1340~1020 cm^(-1)范围内产生强峰。紫外光谱最强吸收峰主要集中200~250和300~350 nm范围,其主要是由HOMO→LUMO+1,HOMO-2→LUMO和HOMO-1→LUMO+2等轨道电子跃迁贡献的。分子表面静电势和局部反应性描述符分析预测极大点和极小点分别大多分布在羟基和氨基的H原子、羰基O原子和N原子较集中的部位附近。前线分子轨道与全局反应性描述符预测头孢他啶(CAZ)药物分子最为活泼,头孢哌酮(CFP)则反之。分子对接显示与HSA之间的作用力以疏水作用力、氢键、π-阳离子相互作用为主,并验证静电势分析结果。该研究基于密度泛函理论获得的非前药型第三代头孢菌素的光谱信息和结构性质规律,可为仿制品制备中的质量控制,衍生物的新药筛选开发,作用机理的理解分析等提供重要信息。Many cephalosporins are widely used,and the structures have specific shared characteristics.However,there is still a lack of systematic comparative research on the property differences between different structures.With the continuous development of research technology,the combination of spectroscopic technology and quantum chemical calculation has become one of the most effective methods to explore structural behavior and observe the electronic structure of drug molecules.This work aimed to systematically and comprehensively analyze the relationship between the structure and properties of non-prodrug-type third-generation cephalosporins.In this study,the density functional theory method X3LYP/6-311+G(d,p)was applied to conduct in-depth research on its geometric structure,infrared spectrum,ultraviolet spectrum,frontier molecular orbital,molecular electrostatic potential,reactivity descriptors,and further molecular docking.The theoretical values including ceftizoxime(CZX),were consistent with the crystal structures.The basic structure of cephalosporin(BSC)is similar in dihedral angle and bond angle,but atoms such as N and O greatly influence the bond length.The IR spectra of ceftazidime(CZX)and cefotaxime(CTX)calculated in theory agree well with the measured values in the experiment.The C O stretching vibration of the non-prodrug-type third-generation cephalosporin carbonyl group is mainly concentrated between 1766 and 1644 cm^(-1).The strong peaks in the range of 1650~1550 cm^(-1) are caused primarily by N—H in-plane bending vibration,and the primary amines will produce strong peaks in the range of 1340~1020 cm^(-1).The most substantial absorption peaks in the UV-Vis spectrum are mainly concentrated in the vicinity of 200~250 and 300~350 nm,and electron orbital transitions,including HOMO,contribute their main components to LUMO+1,HOMO-2 to LUMO,and HOMO-1 to LUMO+2.Molecular surface electrostatic potential and local reactivity descriptors analysis predict that the maxima and minima are mainly distributed near th

关 键 词：非前药 第三代头孢菌素 密度泛函理论 活性位点 分子对接 

分 类 号：R916[医药卫生—药学]