生物大分子晶体学在药物发现中的应用  

Application of Macromolecular X-ray Crystallography in Drug Discovery

作　　者：徐琴[1,2,3] 周欢 郁峰[1,3] 汪启胜 何建华[1,4] XU Qin;ZHOU Huan;YU Feng;WANG Qi-sheng;HE lian-hua(Shanghai Institute of Applied Physies Chinese Academy of Sciences,Shanghai 201800,China;Unioersity ofChinese Academy of Sciences,Beijing 100049,China;Shanghai Synchr Advanced Research Institute Chinese Academy of Sciences,Shanghai 201214,China;The Institute for AdoancedStudies,Wuhan University,Wuhan 430072,China)

机构地区：[1]中国科学院上海应用物理研究所,上海201800 [2]中国科学院大学,北京100049 [3]中国科学院上海高等研究院,上海201204 [4]武汉大学,湖北武汉高等研究院,湖北武汉430072

出　　处：《药物生物技术》2021年第5期513-520,共8页Pharmaceutical Biotechnology

基　　金：国家重点研发计划项目资助(No.2017YFA0504901)。

摘　　要：随着结构生物学自动化程度的提高,通过这一学科提供的详细结构信息在药物发现中得到广泛应用。基于同步辐射的生物大分子X射线晶体学已经被证明是一种结构解析的有力工具,结合药物研发模式的发展,尤其是基于片段的药物研发,使得晶体学结构解析也成为一项筛选技术。该技术能够提供靶标蛋白与小分子片段复合物的结构信息,从而为获得更高的研发效率提供结构基础。文章结合研发模式的进展,具体实例综述了生物大分子X射线晶体学在药物研发中的应用进展。同步辐射装置上的大分子晶体学线站是主要的生物大分子晶体数据采集和结构解析的平台,文章简单介绍了上海光源多条晶体学光束线站性能,晶体学实验步骤,并介绍了自行开发的Aquarium自动处理系统,利用该系统不仅可大幅度提高晶体结构解析的速度,而且由于自动化程度高,极大地降低了晶体学结构解析的技术门槛。文章结合近年来的成功案例进一步说明了基于生物大分子晶体学结构研究技术在药物研发中发挥着越来越重要的作用。With the development of automation in structural biology field,the detailed structural information provided by this discipline has been widely used in drug discovery.Macromolecular X-ray crystallography(MX)based on the synchrotron radiation has been proved to be a powerful tool for the structural determination.Combined with the development of drug discovery paradigm and especially the fragment-based drug discovery method,the X-ray crystallography structure-analysis has also become a screening strategy.It could provide structural information of the complex between the target protein and the small molecule fragment,so as to obtain higher research and development(R&D)efficiency by the structural basis.In this paper,combined with the progress of R&D models,the application progress of MX in drug R&D was reviewed.The MX beamlines on the synchronous radiation facilities are the main platforms for the crystallographic data acquisition and the structural analysis of the macromolecules worldwide.The performance of several MX beamlines at Shanghai synchrotron radiation facility(SSRF),the experimental steps for crystallography and the Aquarium pipeline developed by BL17 U1 at SSRF were briefly introduced.The Aquarium pipeline is an automatic processing system which could not only greatly improve the speed of crystal structure analysis,but also greatly reduce the technical threshold of crystallographic structure analysis due to the high-degree automation.At last,it is illustrated that the MX based on the synchronic radiation plays an increasingly important role in drug discovery by the successful cases in recent years.

关 键 词：生物大分子晶体学 药物发现 上海光源 同步辐射 基于结构的药物发现 Aquarium自动处理系统 

分 类 号：R914[医药卫生—药物化学]