源于天然的酶抑制剂高效发现及评价新技术:进展与展望  

New technologies for efficient discovery and evaluation of natural enzyme inhibitors:Research progress and perspectives

作　　者：赵东方 何荣景 侯旭东 纪东瑞 张庆华 王平 葛广波 ZHAO Dongfang;HE Rongjing;HOU Xudong;JI Dongrui;ZHANG Qinghua;WANG Ping;GE Guangbo(Institute of Interdisciplinary Integrative Medicine Research,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China;Shanghai Huaying Biomedical Technology Co.,Ltd,Shanghai 201203,China)

机构地区：[1]上海中医药大学交叉科学研究院,上海201203 [2]上海华盈生物医药科技有限公司,上海201203

出　　处：《上海中医药大学学报》2021年第1期1-11,19,共12页Academic Journal of Shanghai University of Traditional Chinese Medicine

基　　金：国家自然科学基金资助项目(81922070,81973286,81773687);国家重点研发计划基金资助项目(2017YFC1700200,2017YFC1702000);上海市优秀学术带头人计划资助项目(18XD1403600).

摘　　要：从自然界广泛存在的药用资源中发现活性天然产物,进而作为先导化合物是创新药物研发的重要途径。然而,如何从成分复杂多样的动植物或微生物提取物中高效发现对目标酶具有强效抑制作用的天然产物,一直是酶抑制剂类药物研发领域面临的一大挑战。近年来,随着生命科学及计算机虚拟筛选等技术的蓬勃发展,加之现代分离分析技术的革新和相关前沿技术的突飞猛进,涌现出了多种高效发现和高通量筛选酶抑制剂的新技术与新方法。结合该领域的新近研究进展,着重介绍酶抑制剂发现领域的新方法与新技术,包括计算机虚拟筛选与人工智能识别技术、谱效结合、亲和超滤质谱技术、靶标键合色谱技术、基于光学底物的高通量筛选技术、基于酶活性的蛋白质组分析、基于赖氨酸标记的生物质谱以及蛋白芯片技术等,并对技术原理、优缺点和应用领域做了进一步阐述,且结合具体实例分享了上述前沿技术在酶抑制剂高效发现与抑制效应评价和抑制机制研究中的应用;同时,对如何实现更为高效、精确的酶抑制剂筛选和发现提出了展望,以期为源于天然的酶抑制剂高效发现及相关药理学研究提供系列关键技术及研究思路。Discovery of the natural bioactive products from natural pharmaceutical resources as leading compounds is the major sources for the development of new drugs. However, in the fields of research and development of enzyme inhibitor agents, how to efficiently identify the natural products with strong inhibitory effect on target enzymes from the complex and diverse extracts of animals, plants or microorganisms, is still a big challenge. In recent years, with the vigorous development of life sciences and computer-aided virtual screening technology, as well as the innovation of modern separation and analytical techniques and related frontier technology, series of novel methods and technologies for efficient discovery and high-throughput screening of enzyme inhibitors have emerged. Based on the frontier research progress in this field, this paper reviews the new technologies and methodologies for efficient discovery and high-throughput screening of enzyme inhibitors, including computer-aided virtual screening and artificial intelligence based identification, fingerprint-efficacy correlation, affinity mass spectrometry, target enzyme binding biochromatography, optical substrate based high-throughput screening, activity-based protein profiling, lysine labeling based biomass spectrometry and protein microarray. This review covers the principles,the advantages and disadvantages and the application fields of the above-mentioned cutting-edge technologies,and also shares the cases in rapid discovery of enzyme inhibitors,assessment of inhibition potency and investigation of inhibitory mechanism by using the above-mentioned cutting-edge technologies. Meanwhile,how to achieve more efficient and accurate screening and discovery of enzyme inhibitors is prospected. It is expected that this review could provide series of new technologies and research ideas for rapid discovery of enzyme inhibitors from natural resources and for facilitating the related pharmacological research.

关 键 词：药物发现 酶抑制剂 高通量筛选 计算机虚拟筛选 蛋白芯片 

分 类 号：R914[医药卫生—药物化学]