分子动力学模拟结合相溶解度研究非诺贝特与甲基-β-环糊精的包合行为  

Probing the Encapsulation of Fenofibrate with Hydroxypropyl-β-Cyclodextrin Through Molecular Dynamics Simulation and Experimental Characterization

作　　者：邢雨霖 沈文康 王佳瑜[2] 洪伟铭 张金基 艾凤伟 Xing Yulin;Shen Wenkang;Wang Jiayu;Hong Weiming;Zhang Jinji;Ai Fengwei(School of Pharmacy,Xuzhou Medical University,Xuzhou 221004,China;Jiangsu Provincial Key Laboratory of Central Nervous System Drugs,Pharmaceutical Research Institute of Jiangsu Nhwa Pharmaceutical Co.,Ltd,Xuzhou 221000,China)

机构地区：[1]徐州医科大学药学院,江苏徐州221004 [2]江苏恩华药业股份有限公司药物研究院江苏省中枢神经药物研究重点实验室,江苏徐州221000

出　　处：《山东化工》2024年第7期5-8,共4页Shandong Chemical Industry

基　　金：江苏省高等学校大学生实践创新训练计划项目(202210313095Y)。

摘　　要：目的:研究甲基-β-环糊精(RMβCD)对非诺贝特(FNB)增溶能力和包合机理。方法:以FNB和RMβCD为模型药物和增溶载体,通过相溶解度法结合分子动力学模拟研究FNB-RMβCD包合物中主客体分子的相互作用和结合过程的动态变化。结果:FNB与RMβCD的相溶解度曲线属于A_(L)型,形成1∶1物质的量比的包合物,25,35,45℃三个温度下的包合稳定常数K_(S)分别为4 969.90,5 833.21,7 141.07 L·mol^(-1),分子对接中通过分子间作用力FNB的苯环部分从环糊精大口一侧进入疏水空腔中。200 ns的分子动力学模拟中,FNB、RMβCD和包合物的RMSD波动幅度较小。FNB和RMβCD的结合自由能为(-12.76±1.84) kcal/mol,包合物的形成为非外力驱动的自发过程,其中分子力学项是结合自由能的主要贡献者,而溶剂化能对结合自由能呈负面作用。结论:RMβCD对FNB有良好的增溶能力,包合行为是一个自发过程。Objective:To investigate the solubilization ability and inclusion mechanism of fenofibrate(FNB)by methyl-β-cyclodextrin(RMβCD).Methods:Phase solubility method in conjunction with molecular dynamics simulation was used to study the dynamic changes of host-guest molecules interaction and binding process in FNB-RMβCD inclusion complex using FNB and RMβCD as model drug and solubilization carrier.Results:The phase solubility curve of FNB and RMβCD was A_(L) type,forming a 1∶1 molar ratio of inclusion complex.The inclusion stability constant K_(S) at 25,35 and 45℃were 4969.90,5833.21 and 7141.07 L·mol^(-1),respectively.In molecular docking,the benzene ring part of FNB enters the hydrophobic cavity from the large mouth side of cyclodextrin by intermolecular forces.The RMSD of FNB,RMβCD,and inclusion complexes fluctuated less in 200 ns molecular dynamics simulations.The binding free energy of FNB and RMβCD was(-12.76±1.84)kcal/mol,and the formation of inclusion complexes was a spontaneous process not driven by external forces.The molecular mechanics term was the main contributor to the binding free energy,and the solvation energy had a negative effect on the binding free energy.Conclusion:RMβCD has a good solubilization ability for FNB,and the inclusion behavior is a spontaneous process.

关 键 词：非诺贝特 包合物 分子对接 分子动力学 包合机理 

分 类 号：TQ021[化学工程]