摘要
目的:利用分子动力学模拟方法研究在缩宫素水溶液中的三氯叔丁醇替代物。方法:在25 nm×25 nm×25 nm立方体中放入15个缩宫素、分散剂和约10 000个水分子构建模拟体系,以Gromacs软件采用AMBER03力场计算,采用正则系综(NVT)在300 K下模拟10 ns,通过轨迹计算各种参数。结果:6个体系的缩宫素从同一个起始位置开始模拟,到10 ns的终点时,缩宫素在纯水中逐步趋向于聚集,加入甘露醇、聚乙二醇400、苯丙氨酸、缬氨酸、三氯叔丁醇后呈现不同程度的分散状态。以缩宫素之间的分布情况考察,甘露醇和缬氨酸相当,略优于苯丙氨酸和聚乙二醇400,优于三氯叔丁醇。从相互作用来看,与缩宫素和水两者都有较强相互作用的分散剂效果较好。从参与相互作用的残基来分析,极性作用为主的分散剂分散效果更好。结论:缩宫素在水中有自聚的倾向,甘露醇、聚乙二醇400、苯丙氨酸、缬氨酸能够起到分散剂的作用,具备替代三氯叔丁醇的可能性。
Objective： To search the substitutes of chlorobutanol in oxytocin injection solution by molecular dynamic（ MD） simulation method. Methods： 15 oxytocin molecules,different dispersants and 10 000 water molecules were added into a 25 nm × 25 nm × 25 nm cube box. The structures of dispersants and oxytocin were constructed with Schrodinger software and saved as mol2 format. Simulation systems were established with AMBERTOOL12,and then transferred into Gromacs format. AMBER03 was used as force field in molecular dynamic simulations. The simulation time was 10 ns at 300 K. Diffusion coefficient,interaction energy,hydrogen bond and interaction residues were calculated. Results： Oxytocin molecules were placed at the same position for six MD systems. In aqueous solution,oxytocin tended to gather gradually during MD simulation period. The addition of mannitol,PEG400,phenylalanine,valine and chlorobutanol can inhibit the aggregation of oxytocin. According to the atom numbers from surrounding molecules of oxytocin,mamnitol and valine have equal good dispersing effect for oxytocin,and slightly better than that of phenylalanine and PEG400. The dispersion effect of chlorobutanol is weakest amongall dispersants. The interaction energies between oxytocin,water and dispersants were calculated. Good dispersants have both strong interactions with oxytocin and water. The types of residue participating in interaction were analyzed. The dispersants interacted with oxytocin by polar action have good dispersion effect than by nonpolar action. Conclusion： Oxytocin tends to aggregate in solution. The addition of dispersants into solution can prevent oxytocin from aggregating. Mannitol,PEG400,phenylalanine,valine have good dispersion effect than chlorobutanol,and have the possibilities to replace chlorobutanol in oxytocin solution.
作者
徐亦奇
张媛
孟凡翠
任玉
谭德讲
梅玫
XU Yi-qi;ZHANG Yuan;MENG Fan-cui;REN Yu;TAN De-jiang;MEI Mei(Basic Medical College,Tianjin Medical University,Tianjin 300070,China;National Institutes for Food and Drug Control,Beijing 100050,China;State Key Laboratory of Drug Delivery Technology and Pharmacokinetics,Tianjin Key Laboratory of Molecular Design and Drug Discovery,Tianjin Institute of Pharmaceutical Research,Tianjin 300193,China)
出处
《中国新药杂志》
CAS
CSCD
北大核心
2018年第19期2238-2244,共7页
Chinese Journal of New Drugs
基金
国家"重大新药创制"科技重大专项资助项目(2015ZX09303001)
国家自然科学基金面上项目(81673026)
天津市科委应用基础与前沿计划重点项目(16JCZDJC34800)
关键词
缩宫素
三氯叔丁醇
分子动力学模拟
分散作用
相互作用
oxytocin
chlorobutanol
molecular dynamic simulation
dispersion effect
interaction energy
