分子动力学模拟研究利妥昔单抗国际标准品中人血清白蛋白的活性保护机制  

Protective mechanism of human serum albumin for rituximab international standard by molecular dynamics simulation method

作　　者：俞小娟 李萌[1] 于传飞[1] 武刚[1] 段茂芹 徐刚领 刘春雨[1] 杨雅岚[1] 郭璐韵 崔春博 王文波[1] 郭莎[1] 房森彪 王兰[1] YU Xiao-juan;LI Meng;YU Chuan-fei;WU Gang;DUAN Mao-qin;XU Gang-ling;LIU Chun-yu;YANG Ya-lan;GUO Lu-yun;CUI Chun-bo;WANG Wen-bo;GUO Sha;FANG Sen-biao;WANG Lan(Key Laboratory of the Ministry of Health for Research on Quality and Standardization of Biotech Products,National Institutes for Food and Drug Control,Beijing 102629,China;Department of Molecular Pharmacology,Tianjin Medical University Cancer Institute&Hospital,Tianjin 300060,China)

机构地区：[1]中国食品药品检定研究院卫生部生物技术产品检定及标准化重点实验室/国家药品监督管理局生物制品质量研究与评价重点实验室,北京102629 [2]天津医科大学肿瘤医院国家肿瘤临床医学研究中心/肿瘤分子药理研究室,300060

出　　处：《中国医药生物技术》2023年第4期289-297,共9页Chinese Medicinal Biotechnology

基　　金：国家重点研发计划(2021YFF0600804)。

摘　　要：目的研究利妥昔单抗(rituximab)国际标准品中不同比例人血清白蛋白(HSA)作为冻干保护剂对蛋白分子的保护作用及其作用机制。方法使用Gromacs5.0.5工具包,在300 K的温度条件下,运用计算机模拟的方法,搭建模型,分别模拟分析HSA与利妥昔抗原结合片段(Fab)的分子数比分别为1:1、2:1和3:1状态下的分子结构,从结构生物学的角度比较并分析不同比例人血清白蛋白对利妥昔分子的保护机制。结果不同比例的HSA保护剂在一定程度上可以通过与rituximab Fab分子的相互作用来改善蛋白分子表面的亲疏水性质,阻止无规则卷曲结构的形成,从而保护rituximab Fab的天然构象不被破坏,且在1:1、2:1和3:1三种模拟体系中,HSA与rituximab Fab的分子数比例为2:1时保护效果最好。结论当人血清白蛋白与利妥昔Fab的分子数比为2:1保护效果最佳,可为其他单抗标准品的开发提供参考依据。Objective To study the protective effect and mechanism of different proportions of human serum albumin(HSA)as lyophilized protective agent on rituximab international standard substance.Methods Gromacs5.0.5 kit was used to simulate and analyze the molecular structure of HSA and rituximab Fab with the molecular number ratio of 1:1,2:1 and 3:1,respectively,under the condition of 300 K system.The protective mechanism of different proportions of HSA on rituximab Fab was compared and analyzed from the perspective of structural biology.Results Various HSA ratios improved the hydrophilic and hydrophobic properties of protein molecular surfaces to a certain extent through interaction with rituximab Fab molecules.This prevented the formation of irregular curling structures,thereby protecting the natural conformation of rituximab Fab from destruction.Among the three simulated systems of 1:1,2:1,and 3:1,the protective effect was best when the molecular number ratio of HSA to rituximab Fab was 2:1.Conclusion The protection effect is the best under the molecular number ratio of 2:1 for HSA to rituxifab,which can provide reference for the development of other monoclonal antibody reference materials.

关 键 词：利妥昔国际标准品 单克隆抗体 分子动力学模拟 活性保护 

分 类 号：R95[医药卫生—药学]