首页 期刊 论文 学科刊群 资讯 加盟 关于
EN
image
Article(id=1308468712672092341, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308468301072458736, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2025-0900, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1753977600000, receivedDateStr=2025-08-01, revisedDate=1758729600000, revisedDateStr=2025-09-25, acceptedDate=null, acceptedDateStr=null, onlineDate=1789892851274, onlineDateStr=2026-09-20, pubDate=1765468800000, pubDateStr=2025-12-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1789892851274, onlineIssueDateStr=2026-09-20, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1789892851274, creator=13701087609, updateTime=1789892851274, updator=13701087609, issue=Issue{id=1308468301072458736, tenantId=1146029695717560320, journalId=1189982191388893191, year='2025', volume='60', issue='12', pageStart='3545', pageEnd='3798', issueExtLink='null', onlineDate='null', pubDate='1765468800000', pubDateStr='2025-12-12', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1789892753141, creator='13701087609', updateTime=1789893218933, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1308470254842175559, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308468301072458736, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1308470254842175560, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308468301072458736, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=3692, endPage=3700, ext={EN=ArticleExt(id=1308468712844058806, articleId=1308468712672092341, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Advances in mass spectrometry techniques for characterizing plasma protein binding of covalent inhibitors, columnId=1190335348648547107, journalTitle=Acta Pharmaceutica Sinica, columnName=Reviews, runingTitle=null, highlight=null, articleAbstract=

Covalent inhibitors can realize specific binding by forming covalent bonds with the target, which can realize long-lasting inhibition of the target while reducing the dosage, and to a certain extent, they have overcome the traditional targets that are difficult to become drugs, and they have shown unique advantages in drug discovery and development. The binding characteristics of covalent inhibitors to plasma proteins are closely related to the efficacy, in vivo metabolism, and toxic side effects of these drugs, but the current research in this field is still limited, and there is a lack of systematic studies on the binding of covalent inhibitors of different warheads to high abundance proteins in human blood. Meanwhile, mass spectrometry has become an important tool to characterize the binding of covalent inhibitors to plasma proteins, and mass spectrometry-based proteomics can be used to comprehensively investigate the binding rate, binding reversibility, binding influencing factors, binding protein species, and binding sites of covalent inhibitors to plasma proteins. In this paper, the warheads of covalent inhibitors, the binding characteristics of covalent inhibitors to blood proteins and the research progress of mass spectrometry in the binding of covalent inhibitors to plasma proteins in recent years are reviewed to provide a reference for the study of binding of this class of drugs to plasma proteins.

, authors=Shu-ze XIAN, Zhe WANG, Xuan XU, Sheng-yuan XU, Ning SHENG, Jin-lan ZHANG*, authorsList=Shu-ze XIAN, Zhe WANG, Xuan XU, Sheng-yuan XU, Ning SHENG, Jin-lan ZHANG, authorCompany=null, correspAuthors=Jin-lan ZHANG, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2025 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, fund=null), CN=ArticleExt(id=1308468713678725309, articleId=1308468712672092341, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=共价抑制剂血浆蛋白结合特征的质谱分析技术研究进展, columnId=1190335349655180086, journalTitle=药学学报, columnName=综述, runingTitle=null, highlight=null, articleAbstract=

共价抑制剂通过与靶点形成共价键实现特异性结合, 可以在降低给药剂量的同时实现对靶点的长效抑制, 一定程度上攻克了传统难以成药的靶点, 在药物研发中展现出独特优势。共价抑制剂与血浆蛋白的结合特征与该类药物的药效、体内代谢特点以及毒副作用密切相关, 但目前对于该领域的研究还较为局限, 缺乏对不同弹头共价抑制剂与人血液中高丰度蛋白质结合的系统研究。同时, 质谱分析技术已经成为共价抑制剂与血浆蛋白结合特征研究的重要手段, 通过基于质谱的蛋白组学技术可以对共价抑制剂与血浆蛋白结合率、结合可逆性、结合影响因素、结合蛋白质种类及结合位点进行全面考察。本文对共价抑制剂的弹头、共价抑制剂与血浆蛋白结合特点及近年来质谱分析技术在共价抑制剂与血浆蛋白结合方面的研究进展进行综述, 为该类药物与血液中蛋白质结合研究提供参考。

, authors=贤姝泽, 王喆, 许轩, 徐晟源, 生宁, 张金兰*, authorsList=贤姝泽, 王喆, 许轩, 徐晟源, 生宁, 张金兰, authorCompany=null, correspAuthors=张金兰, authorNote=

作者贡献:

贤姝泽完成文献调研、归纳分析和文章撰写; 许轩、徐晟源负责文献补充; 生宁负责理论指导和修改审校; 张金兰、王喆负责全程指导和修改审校。

, correspAuthorsNote=
张金兰, Tel: 86-10-50927323, Fax: 86-10-63017757, E-mail:
, copyrightStatement=版权所有©《药学学报》编辑部2025, copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=e5+24joYs1dxqxLI208O+g==, magXml=rwBz7mwA4OngPfWemv74KQ==, pdfUrl=null, pdf=AJcRBlqS18isiIVgeUhAaA==, pdfFileSize=1091288, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=b1HGJiYFJL3K9RHqiVhONQ==, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=CIqEHW8/5+vNtzpw92UR1w==, mapNumber=null, fund=null)}, authors=[Author(id=1308499676853273477, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, orderNo=0, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1308499676920382343, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, authorId=1308499676853273477, language=EN, stringName=Shu-ze XIAN, firstName=Shu-ze, middleName=null, lastName=XIAN, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1308499676983296904, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, authorId=1308499676853273477, language=CN, stringName=贤姝泽, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1308499676752610177, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, xref=null, ext=[AuthorCompanyExt(id=1308499676760998786, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, companyId=1308499676752610177, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1308499676773581699, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, companyId=1308499676752610177, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050)])]), Author(id=1308499677071377290, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, orderNo=1, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1308499677146874764, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, authorId=1308499677071377290, language=EN, stringName=Zhe WANG, firstName=Zhe, middleName=null, lastName=WANG, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1308499677205595021, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, authorId=1308499677071377290, language=CN, stringName=王喆, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1308499676752610177, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, xref=null, ext=[AuthorCompanyExt(id=1308499676760998786, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, companyId=1308499676752610177, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1308499676773581699, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, companyId=1308499676752610177, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050)])]), Author(id=1308499677260120975, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, orderNo=2, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1308499677331424145, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, authorId=1308499677260120975, language=EN, stringName=Xuan XU, firstName=Xuan, middleName=null, lastName=XU, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1308499677385950098, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, authorId=1308499677260120975, language=CN, stringName=许轩, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1308499676752610177, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, xref=null, ext=[AuthorCompanyExt(id=1308499676760998786, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, companyId=1308499676752610177, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1308499676773581699, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, companyId=1308499676752610177, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050)])]), Author(id=1308499677448864660, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, orderNo=3, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1308499677515973526, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, authorId=1308499677448864660, language=EN, stringName=Sheng-yuan XU, firstName=Sheng-yuan, middleName=null, lastName=XU, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1308499677583082391, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, authorId=1308499677448864660, language=CN, stringName=徐晟源, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1308499676752610177, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, xref=null, ext=[AuthorCompanyExt(id=1308499676760998786, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, companyId=1308499676752610177, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1308499676773581699, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, companyId=1308499676752610177, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050)])]), Author(id=1308499679252415385, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, orderNo=4, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1308499679365661595, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, authorId=1308499679252415385, language=EN, stringName=Ning SHENG, firstName=Ning, middleName=null, lastName=SHENG, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1308499679453741980, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, authorId=1308499679252415385, language=CN, stringName=生宁, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1308499676752610177, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, xref=null, ext=[AuthorCompanyExt(id=1308499676760998786, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, companyId=1308499676752610177, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1308499676773581699, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, companyId=1308499676752610177, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050)])]), Author(id=1308499679541822366, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, orderNo=5, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=zhjl@imm.ac.cn, emailSecond=null, emailThird=null, correspondingAuthor=1, authorType=1, ext={EN=AuthorExt(id=1308499679642485664, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, authorId=1308499679541822366, language=EN, stringName=Jin-lan ZHANG, firstName=Jin-lan, middleName=null, lastName=ZHANG, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=*, address=State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1308499679722177441, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, authorId=1308499679541822366, language=CN, stringName=张金兰, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=*, address=中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1308499676752610177, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, xref=null, ext=[AuthorCompanyExt(id=1308499676760998786, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, companyId=1308499676752610177, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1308499676773581699, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, companyId=1308499676752610177, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050)])])], keywords=[Keyword(id=1308499679927698338, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, language=EN, orderNo=1, keyword=plasma protein), Keyword(id=1308499679978029987, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, language=EN, orderNo=2, keyword=mass spectrometry), Keyword(id=1308499680032555940, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, language=EN, orderNo=3, keyword=covalent inhibitor), Keyword(id=1308499680091276197, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, language=EN, orderNo=4, keyword=proteomics), Keyword(id=1308499680162579366, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, language=EN, orderNo=5, keyword=protein binding), Keyword(id=1308499680225493927, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, language=CN, orderNo=1, keyword=血浆蛋白), Keyword(id=1308499680292602792, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, language=CN, orderNo=2, keyword=质谱分析法), Keyword(id=1308499680351323049, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, language=CN, orderNo=3, keyword=共价抑制剂), Keyword(id=1308499680414237610, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, language=CN, orderNo=4, keyword=蛋白质组学), Keyword(id=1308499680472957867, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, language=CN, orderNo=5, keyword=蛋白质结合)], refs=[Reference(id=1308499681467007926, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=1, rfOrder=0, authorNames=null, journalName=null, refType=null, unstructuredReference=Baillie TA. Targeted covalent inhibitors for drug design [J]. Angew Chem Int Ed Engl, 2016, 55: 13408-13421., articleTitle=null, refAbstract=null), Reference(id=1308499681525728183, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=2, rfOrder=1, authorNames=null, journalName=null, refType=null, unstructuredReference=Péczka N, Orgován Z, Ábrányi-Balogh P, et al. Electrophilic warheads in covalent drug discovery: an overview [J]. Expert Opin Drug Discov, 2022, 17: 413-422., articleTitle=null, refAbstract=null), Reference(id=1308499681588642744, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=3, rfOrder=2, authorNames=null, journalName=null, refType=null, unstructuredReference=Dalton SE, Di Pietro O, Hennessy E. A medicinal chemistry perspective on FDA-approved small molecule drugs with a covalent mechanism of action [J]. J Med Chem, 2025, 68: 2307-2313., articleTitle=null, refAbstract=null), Reference(id=1308499681668334521, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=4, rfOrder=3, authorNames=null, journalName=null, refType=null, unstructuredReference=Ou J, Zheng J, Huang J, et al. Interaction of acrylamide, acrolein, and 5-hydroxymethylfurfural with amino acids and DNA [J]. J Agric Food Chem, 2020, 68: 5039-5048., articleTitle=null, refAbstract=null), Reference(id=1308499681731249082, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=5, rfOrder=4, authorNames=null, journalName=null, refType=null, unstructuredReference=Du H, Zhang X, Wu Z, et al. CovalentInDB 2.0: an updated comprehensive database for structure-based and ligand-based covalent inhibitor design and screening [J]. Nucleic Acids Res, 2025, 53: D1322-D1327., articleTitle=null, refAbstract=null), Reference(id=1308499681802552251, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=6, rfOrder=5, authorNames=null, journalName=null, refType=null, unstructuredReference=Gao M, Moumbock AFA, Qaseem A, et al. CovPDB: a high-resolution coverage of the covalent protein-ligand interactome [J]. Nucleic Acids Res, 2021, 50: D445-D450., articleTitle=null, refAbstract=null), Reference(id=1308499681873855420, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=7, rfOrder=6, authorNames=null, journalName=null, refType=null, unstructuredReference=Knox C, Wilson M, Klinger CM, et al. DrugBank 6.0: the DrugBank Knowledgebase for 2024 [J]. Nucleic Acids Res, 2024, 52: D1265-D1275., articleTitle=null, refAbstract=null), Reference(id=1308499681970324413, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=8, rfOrder=7, authorNames=null, journalName=null, refType=null, unstructuredReference=Dömötör O, Pelivan K, Borics A, et al. Comparative studies on the human serum albumin binding of the clinically approved EGFR inhibitors gefitinib, erlotinib, afatinib, osimertinib and the investigational inhibitor KP2187 [J]. J Pharm Biomed Anal, 2018, 154: 321-331., articleTitle=null, refAbstract=null), Reference(id=1308499682033238974, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=9, rfOrder=8, authorNames=null, journalName=null, refType=null, unstructuredReference=Wind S, Schnell D, Ebner T, et al. Clinical pharmacokinetics and pharmacodynamics of afatinib [J]. Clin Pharmacokinet, 2017, 56: 235-250., articleTitle=null, refAbstract=null), Reference(id=1308499683698377663, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=10, rfOrder=9, authorNames=null, journalName=null, refType=null, unstructuredReference=Ballard TE, Dahal UP, Bessire AJ, et al. A tag-free collisionally induced fragmentation approach to detect drug-adducted proteins by mass spectrometry [J]. Rapid Commun Mass Spectrom, 2015, 29: 2175-2183., articleTitle=null, refAbstract=null), Reference(id=1308499683790652352, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=11, rfOrder=10, authorNames=null, journalName=null, refType=null, unstructuredReference=Jiang SL, Li L, Hu L, et al. Comprehending binding features between ibrutinib and human alpha-1 acid glycoprotein: combined experimental approaches and theoretical simulations [J]. Spectrochim Acta A Mol Biomol Spectrosc, 2023, 285: 121834., articleTitle=null, refAbstract=null), Reference(id=1308499683857761217, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=12, rfOrder=11, authorNames=null, journalName=null, refType=null, unstructuredReference=Muste C, Gu C. BTK-inhibitor drug covalent binding to lysine in human serum albumin using LC-MS/MS [J]. Drug Metab Pharmacokinet, 2022, 42: 100433., articleTitle=null, refAbstract=null), Reference(id=1308499683912287170, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=13, rfOrder=12, authorNames=null, journalName=null, refType=null, unstructuredReference=Wu Y, Chen L, Chen J, et al. Covalent binding mechanism of furmonertinib and osimertinib with human serum albumin [J]. Drug Metab Dispos, 2023, 51: 8-16., articleTitle=null, refAbstract=null), Reference(id=1308499683991978947, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=14, rfOrder=13, authorNames=null, journalName=null, refType=null, unstructuredReference=Kou Sb, Li L, Zhang RJ, et al. Elucidation of the interaction mechanism of olmutinib with human α-1 acid glycoprotein: insights from spectroscopic and molecular modeling studies [J]. J Biomol Struct Dyn, 2023, 41: 525-537., articleTitle=null, refAbstract=null), Reference(id=1308499684054893508, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=15, rfOrder=14, authorNames=null, journalName=null, refType=null, unstructuredReference=Liu XY, Diao XX, Zhong DF. Advancements in the identification of adducts of drug-human serum albumin [J]. Acta Pharm Sin (药学学报), 2024, 59: 886-898., articleTitle=null, refAbstract=null), Reference(id=1308499684109419461, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=16, rfOrder=15, authorNames=null, journalName=null, refType=null, unstructuredReference=Liu X, Feng D, Zheng M, et al. Characterization of covalent binding of tyrosine kinase inhibitors to plasma proteins [J]. Drug Metab Pharmacokinet, 2020, 35: 456-465., articleTitle=null, refAbstract=null), Reference(id=1308499684184916934, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=17, rfOrder=16, authorNames=null, journalName=null, refType=null, unstructuredReference=Hu ZY, Sui HY, Zhong QF, et al. In vitro investigation of the binding characteristics of dacomitinib to human α1-acid glycoprotein: multispectral and computational modeling [J]. Spectrochim Acta A Mol Biomol Spectrosc, 2024, 314: 124197., articleTitle=null, refAbstract=null), Reference(id=1308499684243637191, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=18, rfOrder=17, authorNames=null, journalName=null, refType=null, unstructuredReference=Vuu I, Dahal UP, Wang Z, et al. Absorption, metabolism and excretion of [14C]-sotorasib in healthy male subjects: characterization of metabolites and a minor albumin-sotorasib conjugate [J]. Cancer Chemother Pharmacol, 2022, 90: 357-367., articleTitle=null, refAbstract=null), Reference(id=1308499684302357448, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=19, rfOrder=18, authorNames=null, journalName=null, refType=null, unstructuredReference=Chen H, Shah A, Kato S, et al. Metabolism and excretion of [14C]mobocertinib, a selective covalent inhibitor of epidermal growth factor receptor (EGFR) exon 20 insertion mutations, in healthy male subjects [J]. Drug Metab Dispos, 2024, 52: 1115-1123., articleTitle=null, refAbstract=null), Reference(id=1308499684365272009, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=20, rfOrder=19, authorNames=null, journalName=null, refType=null, unstructuredReference=Dahal UP, Rock BM, Rodgers J, et al. Absorption, distribution, metabolism, and excretion of [14C]-sotorasib in rats and dogs: interspecies differences in absorption, protein conjugation and metabolism [J]. Drug Metab Dispos, 2022, 50: 600-612., articleTitle=null, refAbstract=null), Reference(id=1308499684432380874, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=21, rfOrder=20, authorNames=null, journalName=null, refType=null, unstructuredReference=Rahbaek L, Cilliers C, Wegerski CJ, et al. Absorption, single-dose and steady-state metabolism, excretion, and pharmacokinetics of adagrasib, a KRASG12C inhibitor [J]. Cancer Chemother Pharmacol, 2024, 95: 7., articleTitle=null, refAbstract=null), Reference(id=1308499684495295435, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=22, rfOrder=21, authorNames=null, journalName=null, refType=null, unstructuredReference=Meng J, Liu XY, Ma S, et al. Metabolism and disposition of pyrotinib in healthy male volunteers: covalent binding with human plasma protein [J]. Acta Pharmacol Sin, 2019, 40: 980-988., articleTitle=null, refAbstract=null), Reference(id=1308499684554015692, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=23, rfOrder=22, authorNames=null, journalName=null, refType=null, unstructuredReference=Ajmal MR, Abdelhameed AS, Alam P, et al. Interaction of new kinase inhibitors cabozantinib and tofacitinib with human serum alpha-1 acid glycoprotein. A comprehensive spectroscopic and molecular docking approach [J]. Spectrochim Acta A Mol Biomol Spectrosc, 2016, 159: 199-208., articleTitle=null, refAbstract=null), Reference(id=1308499684616930253, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=24, rfOrder=23, authorNames=null, journalName=null, refType=null, unstructuredReference=Greenfield SR, Eng H, Yang Q, et al. Species differences in plasma protein binding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease inhibitor nirmatrelvir [J]. Xenobiotica, 2023, 53: 12-24., articleTitle=null, refAbstract=null), Reference(id=1308499684700816334, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=25, rfOrder=24, authorNames=null, journalName=null, refType=null, unstructuredReference=Griffith DC, Loutit JS, Morgan EE, et al. Phase 1 study of the safety, tolerability, and pharmacokinetics of the β-lactamase inhibitor vaborbactam (RPX7009) in healthy adult subjects [J]. Antimicrob Agents Chemother, 2016, 60: 6326-6332., articleTitle=null, refAbstract=null), Reference(id=1308499684793091023, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=26, rfOrder=25, authorNames=null, journalName=null, refType=null, unstructuredReference=Al Jalali V, Wölfl-Duchek M, Taubert M, et al. Plasma and soft tissue pharmacokinetics of ceftolozane/tazobactam in healthy volunteers after single and multiple intravenous infusion: a microdialysis study [J]. J Antimicrob Chemother, 2021, 76: 2342-2351., articleTitle=null, refAbstract=null), Reference(id=1308499684885365712, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=27, rfOrder=26, authorNames=null, journalName=null, refType=null, unstructuredReference=Xu L, Peng CC, Dawson K, et al. Metabolism, pharmacokinetics and excretion of [14C]dimethyl fumarate in healthy volunteers: an example of xenobiotic biotransformation following endogenous metabolic pathways [J]. Xenobiotica, 2023, 53: 163-172., articleTitle=null, refAbstract=null), Reference(id=1308499684973446097, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=28, rfOrder=27, authorNames=null, journalName=null, refType=null, unstructuredReference=Abdelhameed AS, Alam P, Khan RH. Binding of Janus kinase inhibitor tofacitinib with human serum albumin: multi-technique approach [J]. J Biomol Struct Dyn, 2016, 34: 2037-2044., articleTitle=null, refAbstract=null), Reference(id=1308499685032166354, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=29, rfOrder=28, authorNames=null, journalName=null, refType=null, unstructuredReference=Favinha AG, Barreiro DS, Martins JN, et al. Acrylamide-hemoglobin adduct: a spectroscopic study [J]. Spectrochim Acta A Mol Biomol Spectrosc, 2020, 241: 118644., articleTitle=null, refAbstract=null), Reference(id=1308499685090886611, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=30, rfOrder=29, authorNames=null, journalName=null, refType=null, unstructuredReference=Gu TJ, Cai J, Auster A, et al. In vitro metabolism of targeted covalent inhibitors and their thiol conjugates by gut microbiome from rats, mice, and humans [J]. Drug Metab Dispos, 2025, 53: 100027., articleTitle=null, refAbstract=null), Reference(id=1308499685174772692, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=31, rfOrder=30, authorNames=null, journalName=null, refType=null, unstructuredReference=Hossain MA, Brahme RR, Miller BC, et al. Mass spectrometry methods and mathematical PK/PD model for decision tree-guided covalent drug development [J]. Nat Commun, 2025, 16: 1777., articleTitle=null, refAbstract=null), Reference(id=1308499685237687253, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=32, rfOrder=31, authorNames=null, journalName=null, refType=null, unstructuredReference=Sun LL, Liu XW. Membrane ultrafiltration-based sample preparation method and sheath-flow CZE-MS/MS for top-down proteomics [M] // Yang ZC, Sun LL. Methods in Molecular Biology. New York: Springer US, 2022: 5-14., articleTitle=null, refAbstract=null), Reference(id=1308499685300601814, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=33, rfOrder=32, authorNames=null, journalName=null, refType=null, unstructuredReference=Shen X, Yang Z, Mccool EN, et al. Capillary zone electrophoresis-mass spectrometry for top-down proteomics [J]. Trends Analyt Chem, 2019, 120: 115644., articleTitle=null, refAbstract=null), Reference(id=1308499685367710679, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=34, rfOrder=33, authorNames=null, journalName=null, refType=null, unstructuredReference=Shan L, Jones BR. Nano-LC: an updated review [J]. Biomed Chromatogr, 2022, 36: e5317., articleTitle=null, refAbstract=null), Reference(id=1308499685439013848, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=35, rfOrder=34, authorNames=null, journalName=null, refType=null, unstructuredReference=Pu F, Ugrin SA, Radosevich AJ, et al. High-throughput intact protein analysis for drug discovery using infrared matrix-assisted laser desorption electrospray ionization mass spectrometry [J]. Anal Chem, 2022, 94: 13566-13574., articleTitle=null, refAbstract=null), Reference(id=1308499685531288537, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=36, rfOrder=35, authorNames=null, journalName=null, refType=null, unstructuredReference=Tailor A, Waddington JC, Meng X, et al. Mass spectrometric and functional aspects of drug-protein conjugation [J]. Chem Res Toxicol, 2016, 29: 1912-1935., articleTitle=null, refAbstract=null), Reference(id=1308499685594203098, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=37, rfOrder=36, authorNames=null, journalName=null, refType=null, unstructuredReference=Duong VA, Lee H. Bottom-up proteomics: advancements in sample preparation [J]. Int J Mol Sci, 2023, 24: 5350., articleTitle=null, refAbstract=null), Reference(id=1308499685661311963, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=38, rfOrder=37, authorNames=null, journalName=null, refType=null, unstructuredReference=Chen W, Wang S, Adhikari S, et al. Simple and integrated spintip-based technology applied for deep proteome profiling [J]. Anal Chem, 2016, 88: 4864-4871., articleTitle=null, refAbstract=null), Reference(id=1308499685732615132, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=39, rfOrder=38, authorNames=null, journalName=null, refType=null, unstructuredReference=Mikšík I. Coupling of CE-MS for protein and peptide analysis [J]. J Sep Sci, 2019, 42: 385-397., articleTitle=null, refAbstract=null), Reference(id=1308499685795529693, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=40, rfOrder=39, authorNames=null, journalName=null, refType=null, unstructuredReference=Rozanova S, Barkovits K, Nikolov M, et al. Quantitative mass spectrometry-based proteomics: an overview [M] // Marcus K, Eisenacher M, Sitek B. Quantitative Methods in Proteomics. New York: Springer US, 2021: 85-116., articleTitle=null, refAbstract=null), Reference(id=1308499685858444254, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=41, rfOrder=40, authorNames=null, journalName=null, refType=null, unstructuredReference=Gong S, Zhuo Y, Chen S, et al. Quantification of osimertinib and metabolite-protein modification reveals its high potency and long duration of effects on target organs [J]. Chem Res Toxicol, 2021, 34: 2309-2318., articleTitle=null, refAbstract=null), Reference(id=1308499685929747423, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=42, rfOrder=41, authorNames=null, journalName=null, refType=null, unstructuredReference=Zhang L, Shen HL. Quantitative accuracy evaluation of mass spectrometry based proteomics methods commonly used in biomarker research [J]. Chem J Chin Univ (高等学校化学学报), 2024, 45: 203-211., articleTitle=null, refAbstract=null), Reference(id=1308499685996856288, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=43, rfOrder=42, authorNames=null, journalName=null, refType=null, unstructuredReference=Brown KA, Gugger MK, Yu Z, et al. Nonionic, cleavable surfactant for top-down proteomics [J]. Anal Chem, 2023, 95: 1801-1804., articleTitle=null, refAbstract=null)], funds=null, companyList=[AuthorCompany(id=1308499676752610177, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, xref=null, ext=[AuthorCompanyExt(id=1308499676760998786, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, companyId=1308499676752610177, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1308499676773581699, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, companyId=1308499676752610177, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050)])], figs=[ArticleFig(id=1308499680636535724, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, language=EN, label=null, caption=null, figureFileSmall=q3QRxJDFVathAtYdHU8Heg==, figureFileBig=7iJDLIDkK5L0WTfQlB0MJQ==, tableContent=null), ArticleFig(id=1308499680703644589, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, language=CN, label=Fig.1, caption=Structural formulae of common covalent inhibitor warheads. A: Acrylamide warheads; B: Nitrile warheads; C: α, β-Unsaturated ketone warheads; D: α-Keto amide warheads; E: Cyclic borate warheads; F: β-Lactam warheads; G: Boric acid warheads, figureFileSmall=q3QRxJDFVathAtYdHU8Heg==, figureFileBig=7iJDLIDkK5L0WTfQlB0MJQ==, tableContent=null), ArticleFig(id=1308499680800113582, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, language=EN, label=null, caption=null, figureFileSmall=Zz0ux+/MAxntenqKIR0vDg==, figureFileBig=UlR10F3E8Om26d0B3YC/IA==, tableContent=null), ArticleFig(id=1308499680858833839, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, language=CN, label=Fig.2, caption=Top-down proteomics workflow, figureFileSmall=Zz0ux+/MAxntenqKIR0vDg==, figureFileBig=UlR10F3E8Om26d0B3YC/IA==, tableContent=null), ArticleFig(id=1308499680913359792, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, language=EN, label=null, caption=null, figureFileSmall=U/Ne34VtJlgN9E7a/zfBLg==, figureFileBig=JgigyDKZTwLSOWOKv+9ZIw==, tableContent=null), ArticleFig(id=1308499680972080049, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, language=CN, label=Fig.3, caption=Bottom-up proteomics workflow, figureFileSmall=U/Ne34VtJlgN9E7a/zfBLg==, figureFileBig=JgigyDKZTwLSOWOKv+9ZIw==, tableContent=null), ArticleFig(id=1308499681039188914, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
WarheadTargeting amino acid binding siteReaction typeReference
AcrylamideCysMichael addition[4]
LysMichael addition[4]
SerNucleophilic substitution[5]
ThrNucleophilic substitution[5]
α, β-Unsaturated ketoneCysComposite reaction, cyclohemiaminoacetalization, Michael addition[6]
HisComposite reaction, Michael addition[6]
LysComposite reaction, imine condensation, Michael addition[6]
ThrComposite reaction, cyclohemiaminoacetalization[6]
ValImine condensation, Michael addition[6]
NitrileCysNucleophilic aliphatic subsititution, nucleophilic addition to a triple bond, nucleophilic aromatic substitution[6]
SerNucleophilic aliphatic subsititution, nucleophilic addition to a triple bond, nucleophilic aromatic substitution[6]
LysNucleophilic aliphatic subsititution, nucleophilic aromatic substitution[6]
β-LactamCysBeta-lactam addition, composite reaction, Michael addition, nucleophilic aliphatic subsititution[6]
SerBeta-lactam addition, composite reaction, nucleophilic aliphatic subsititution[6]
LysBeta-lactam addition, composite reaction, Michael addition, nucleophilic aliphatic subsititution[6]
Boronic acid and cyclic boronateGluBorylation, composite reaction[6]
HisBorylation, composite reaction[6]
LysComposite reaction[6]
SerBorylation, composite reaction[6]
ThrBorylation, composite reaction[6]
α-KetoamideCysNucleophilic addition[5]
SerNucleophilic addition[5]
ThrNucleophilic addition[5]
), ArticleFig(id=1308499681118880691, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, language=CN, label=Tab.1, caption=

Amino acids binding to common warheads and their reaction types

, figureFileSmall=null, figureFileBig=null, tableContent=
WarheadTargeting amino acid binding siteReaction typeReference
AcrylamideCysMichael addition[4]
LysMichael addition[4]
SerNucleophilic substitution[5]
ThrNucleophilic substitution[5]
α, β-Unsaturated ketoneCysComposite reaction, cyclohemiaminoacetalization, Michael addition[6]
HisComposite reaction, Michael addition[6]
LysComposite reaction, imine condensation, Michael addition[6]
ThrComposite reaction, cyclohemiaminoacetalization[6]
ValImine condensation, Michael addition[6]
NitrileCysNucleophilic aliphatic subsititution, nucleophilic addition to a triple bond, nucleophilic aromatic substitution[6]
SerNucleophilic aliphatic subsititution, nucleophilic addition to a triple bond, nucleophilic aromatic substitution[6]
LysNucleophilic aliphatic subsititution, nucleophilic aromatic substitution[6]
β-LactamCysBeta-lactam addition, composite reaction, Michael addition, nucleophilic aliphatic subsititution[6]
SerBeta-lactam addition, composite reaction, nucleophilic aliphatic subsititution[6]
LysBeta-lactam addition, composite reaction, Michael addition, nucleophilic aliphatic subsititution[6]
Boronic acid and cyclic boronateGluBorylation, composite reaction[6]
HisBorylation, composite reaction[6]
LysComposite reaction[6]
SerBorylation, composite reaction[6]
ThrBorylation, composite reaction[6]
α-KetoamideCysNucleophilic addition[5]
SerNucleophilic addition[5]
ThrNucleophilic addition[5]
), ArticleFig(id=1308499681198572468, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
WarheadDrugApproval dateIndicationTargeting amino acid binding sitePlasma protein binding ratioBinding plasma proteins and amino acid binding sitesRef.
AcrylamideAfatinib2013NSCLCCys95%HSA-Lys190HAG[7-9]
Ibrutinib2013MCLCys97.3%HSA-Lys106, 137, 351, 414, 525; Cys34HAG[7, 10-12]
Osimertinib2015NSCLCCys95%HSA-Lys195, 199NR[7, 13]
Olmutinib2016 (Korea)NSCLCCys99%HSA-Lys190, 351, 414, 525, 402; Arg348; Cys34HAG[14, 15]
Neratinib2017Breast cancerCysover 99%HSA-Lys190HAG[7, 16]
Dacomitinib2018NSCLCCys98%HASHAG-His97, Ile88, Arg90[7, 17]
Selinexor2019Multiple myeloma, diffuse large B-cell lymphomaCys95%NRNR[7]
Almonertinib2020NSCLCCysNRNRNRNR
Sotorasib2021NSCLCCys89%HSA-Lys137NR[7, 18]
Mobocertinib2021NSCLCCys96%HSANR[19, 20]
Adagrasib2022NSCLCCys98%HAS-Lys137NR[18, 21]
Futibatinib2022Intrahepatic cholangiocarcinomaCys95%HSAHAG[7]
Pyrotinib2022 (China)Breast cancerCys58%HSA-Lys190NR[22]
Zanubrutinib2023CLLCys94%HSA-Lys262, 351, 414[12]NR[7]
Orelabrutinib2023 (China)MCL, CLLCysNRNRNRNR
Ritlecitinib2023Alopecia areata and rheumatoid arthritisCys14%NRNR[7]
α-KetoamideBoceprevir2011Hepatitis CCys75%NRNR[7]
Telaprevir2011Hepatitis CCys, Ser59%-76%HSA[7]HAG[7]
Narlaprevir2016Hepatitis CCysNRNRNRNR
Boronic acidIxazomib2015Multiple myelomaThr99%NRNR[7]
NitrileTofacitinib2012Rheumatoid arthritisCys40%HSAHAG[7, 23]
Nirmatrelvir2021COVID-19Cys69%HSAHAG[7, 24, 25]
Momelotinib2023MyelofibrosisCys91%NRNR[7]
Cyclic boronateTavaborole2014Fungal infectionAdenosineNRNRNRNR
Crisaborole2016EczemaSer97%NRNR[7]
Vaborbactam2017Bacterial infectionSer33%HSA[7]NR[25]
β-LactamCeftaroline2010AntibioticSer20%NRNR[7]
Ceftolozane2014AntibioticSer6.3%NRNR[26]
Cefiderocol2019AntibioticSer40%-60%HSANR[7]
α, β-Unsaturated ketone warheadsDMF fumarate2013Relapsing-remitting multiple sclerosisCys27%-45% (MMF)HSA-Cys34NR[7, 27]
Vamorolone2023Duchenne muscular dystrophyCys88.1%NRNR[7]
Omaveloxolone2023Friedrich's ataxiaCys97%NRNR[7]
), ArticleFig(id=1308499681303430069, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, language=CN, label=Tab.2, caption=

Summary of covalent inhibitors binding to plasma proteins. NSCLC: Non-small-cell lung cancer; MCL: Mantle cell lymphoma; HSA: Human serum albumin; HAG: Human alpha1-acid glycoprotein; NR: Not reported; CLL: Chronic lymphocytic leukemia

, figureFileSmall=null, figureFileBig=null, tableContent=
WarheadDrugApproval dateIndicationTargeting amino acid binding sitePlasma protein binding ratioBinding plasma proteins and amino acid binding sitesRef.
AcrylamideAfatinib2013NSCLCCys95%HSA-Lys190HAG[7-9]
Ibrutinib2013MCLCys97.3%HSA-Lys106, 137, 351, 414, 525; Cys34HAG[7, 10-12]
Osimertinib2015NSCLCCys95%HSA-Lys195, 199NR[7, 13]
Olmutinib2016 (Korea)NSCLCCys99%HSA-Lys190, 351, 414, 525, 402; Arg348; Cys34HAG[14, 15]
Neratinib2017Breast cancerCysover 99%HSA-Lys190HAG[7, 16]
Dacomitinib2018NSCLCCys98%HASHAG-His97, Ile88, Arg90[7, 17]
Selinexor2019Multiple myeloma, diffuse large B-cell lymphomaCys95%NRNR[7]
Almonertinib2020NSCLCCysNRNRNRNR
Sotorasib2021NSCLCCys89%HSA-Lys137NR[7, 18]
Mobocertinib2021NSCLCCys96%HSANR[19, 20]
Adagrasib2022NSCLCCys98%HAS-Lys137NR[18, 21]
Futibatinib2022Intrahepatic cholangiocarcinomaCys95%HSAHAG[7]
Pyrotinib2022 (China)Breast cancerCys58%HSA-Lys190NR[22]
Zanubrutinib2023CLLCys94%HSA-Lys262, 351, 414[12]NR[7]
Orelabrutinib2023 (China)MCL, CLLCysNRNRNRNR
Ritlecitinib2023Alopecia areata and rheumatoid arthritisCys14%NRNR[7]
α-KetoamideBoceprevir2011Hepatitis CCys75%NRNR[7]
Telaprevir2011Hepatitis CCys, Ser59%-76%HSA[7]HAG[7]
Narlaprevir2016Hepatitis CCysNRNRNRNR
Boronic acidIxazomib2015Multiple myelomaThr99%NRNR[7]
NitrileTofacitinib2012Rheumatoid arthritisCys40%HSAHAG[7, 23]
Nirmatrelvir2021COVID-19Cys69%HSAHAG[7, 24, 25]
Momelotinib2023MyelofibrosisCys91%NRNR[7]
Cyclic boronateTavaborole2014Fungal infectionAdenosineNRNRNRNR
Crisaborole2016EczemaSer97%NRNR[7]
Vaborbactam2017Bacterial infectionSer33%HSA[7]NR[25]
β-LactamCeftaroline2010AntibioticSer20%NRNR[7]
Ceftolozane2014AntibioticSer6.3%NRNR[26]
Cefiderocol2019AntibioticSer40%-60%HSANR[7]
α, β-Unsaturated ketone warheadsDMF fumarate2013Relapsing-remitting multiple sclerosisCys27%-45% (MMF)HSA-Cys34NR[7, 27]
Vamorolone2023Duchenne muscular dystrophyCys88.1%NRNR[7]
Omaveloxolone2023Friedrich's ataxiaCys97%NRNR[7]
)], attaches=null, journal=Journal(id=1189982048455397383, delFlag=0, nameCn=药学学报, nameEn=Acta Pharmaceutica Sinica, nameHistory1=null, nameHistory2=null, issn=0513-4870, eissn=null, cn=11-2163/R, coden=null, periodic=0, language=CN, oaType=null, ccby=null, superviseOffice=null, ownerOffice=null, pubOffice=null, editorOffice=null, officeType=null, aims=null, clcCode=null, officeProv=null, officeCity=null, officeAddr=null, officeZip=null, officeEmail=null, officePhone=null, editDirector=null, officeDirector=null, officeDirectorPhone=null, officeStaffNum=null, officeEmpNum=null, coverPicUrl=BTxjudbJDVO4PqdBR6On6Q==, journalPrice=null, startedYear=null, abbrevIsoEn=null, journalRemark=null, publicationField=null, createdTime=1761643429151, updatedTime=1788948913902, createdBy=18614031015, updatedBy=13041195026, firstLetterCn=Y, firstLetterEn=Y, subjectCode=Medical and Pharmaceutical Sciences, subjectName=null, subjectCodeEn=Medical and Pharmaceutical Sciences, subjectNameEn=null, picCn=BTxjudbJDVO4PqdBR6On6Q==, picEn=c4l1ckL55nWbhl1KrFdWIA==, jcr=null, cjcr=null, exts=[JournalExt(id=1304509553505227679, language=CN, name=药学学报, nameHistory1=null, nameHistory2=null, managedBy=中国科学技术协会, sponsoredBy=中国药学会、中国医学科学院药物研究所, publishedBy=《药学学报》编辑委员会编辑出版, editorOffice=, officeProv=null, officeCity=null, officeAddr=, officeZip=, editDirector=, officeDirector=null, officePhone=null, coverPicUrl=null, journalRemark=, submitArticleUrl=null, websiteUrl=, createdTime=1788948914171, updatedTime=1788948914171, createdBy=13041195026, updatedBy=13041195026, submissionGuidelinesUrl=, submissionAuthorUrl=https://www.yxxb.com.cn/journalx_yxxb/authorLogOn.action, submissionEditorUrl=https://www.yxxb.com.cn/journalx_yxxb/editorLogOn.action, submissionReviewUrl=https://www.yxxb.com.cn/journalx_yxxb/expertLogOn.action, submissionCeEditorUrl=, submissionAeEditorUrl=, option={"copyright":""}), JournalExt(id=1304509553559753632, language=EN, name=Acta Pharmaceutica Sinica, nameHistory1=null, nameHistory2=null, managedBy=, sponsoredBy=, publishedBy=, editorOffice=, officeProv=null, officeCity=null, officeAddr=, officeZip=, editDirector=, officeDirector=null, officePhone=null, coverPicUrl=null, journalRemark=, submitArticleUrl=null, websiteUrl=, createdTime=1788948914184, updatedTime=1788948914184, createdBy=13041195026, updatedBy=13041195026, submissionGuidelinesUrl=, submissionAuthorUrl=https://www.yxxb.com.cn/journalx_yxxb/authorLogOn.action, submissionEditorUrl=https://www.yxxb.com.cn/journalx_yxxb/editorLogOn.action, submissionReviewUrl=https://www.yxxb.com.cn/journalx_yxxb/expertLogOn.action, submissionCeEditorUrl=, submissionAeEditorUrl=, option={"copyright":""})], databaseList=null, tenantJournalId=1189982191388893191, websiteList=[Website(id=1189982271588340489, webName=null, webTitle=null, webDomain=null, webCopyrigh=null, webIpcNo=null, seoTitle=null, seoKeywords=null, seoDescription=null, tenantJournalId=null, journalId=1189982191388893191, journalNameCn=null, journalNameEn=null, grayFlag=null, tenantId=1146029695717560320, platformId=null, journalGroupId=null, journalGroupNameCn=null, journalGroupNameEn=null, type=1, domain=https://castjournals.cast.org.cn/joweb/yxxb/CN, language=CN, createTime=1761643482348, createBy=18614031015, updateTime=1761643498101, updateBy=18614031015, name=药学学报-中文, tplId=1146099689490845704, title=药学学报, delFlag=0, indexPage=/home, props=[WebsiteProps(id=1189982873114448678, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=articleTextType, value=kx, createTime=1761643625763, updateTime=1761643625763, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873093477155, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=banner, value=null, createTime=1761643625758, updateTime=1761643625758, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873135420201, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=grayFlag, value=0, createTime=1761643625768, updateTime=1761643625768, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873085088546, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=logo, value=https://castjournals.cast.org.cn/joweb/yxxb/CN/file/pic?fileId=w+t2v8bJnX5lh3+hRRJcDA==, createTime=1761643625756, updateTime=1761643625756, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873152197419, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=minRunFlag, value=0, createTime=1761643625772, updateTime=1761643625772, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873110254373, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=picServerUrl, value=https://castjournals.cast.org.cn/joweb/yxxb/CN/file/pic, createTime=1761643625762, updateTime=1761643625762, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873143808810, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=silenceFlag, value=0, createTime=1761643625770, updateTime=1761643625770, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873101865764, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=staticResourcePath, value=https://castjournals.cast.org.cn/joweb/cast_kjdb_cn_619/, createTime=1761643625760, updateTime=1761643625760, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873122837287, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=themeColor, value=null, createTime=1761643625765, updateTime=1761643625765, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873127031592, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=themeStyle, value=null, createTime=1761643625766, updateTime=1761643625766, creator=18614031015, updator=18614031015)]), Website(id=1189982271655449355, webName=null, webTitle=null, webDomain=null, webCopyrigh=null, webIpcNo=null, seoTitle=null, seoKeywords=null, seoDescription=null, tenantJournalId=null, journalId=1189982191388893191, journalNameCn=null, journalNameEn=null, grayFlag=null, tenantId=1146029695717560320, platformId=null, journalGroupId=null, journalGroupNameCn=null, journalGroupNameEn=null, type=1, domain=https://castjournals.cast.org.cn/joweb/yxxb/EN, language=EN, createTime=1761643482364, createBy=18614031015, updateTime=1761643514085, updateBy=18614031015, name=药学学报-英文, tplId=1146101810881728533, title=Acta Pharmaceutica Sinica, delFlag=0, indexPage=/home, props=[WebsiteProps(id=1189982903015633534, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=articleTextType, value=kx, createTime=1761643632892, updateTime=1761643632892, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982902990467707, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=banner, value=null, createTime=1761643632886, updateTime=1761643632886, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982903036605057, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=grayFlag, value=0, createTime=1761643632897, updateTime=1761643632897, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982902982079098, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=logo, value=https://castjournals.cast.org.cn/joweb/yxxb/EN/file/pic?fileId=w+t2v8bJnX5lh3+hRRJcDA==, createTime=1761643632884, updateTime=1761643632884, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982903053382275, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=minRunFlag, value=0, createTime=1761643632901, updateTime=1761643632901, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982903007244925, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=picServerUrl, value=https://castjournals.cast.org.cn/joweb/yxxb/EN/file/pic, createTime=1761643632890, updateTime=1761643632890, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982903044993666, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=silenceFlag, value=0, createTime=1761643632899, updateTime=1761643632899, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982902998856316, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=staticResourcePath, value=https://castjournals.cast.org.cn/joweb/cast_kjdb_en_623/, createTime=1761643632888, updateTime=1761643632888, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982903019827839, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=themeColor, value=null, createTime=1761643632893, updateTime=1761643632893, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982903028216448, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=themeStyle, value=null, createTime=1761643632895, updateTime=1761643632895, creator=18614031015, updator=18614031015)])], journalTitle=药学学报, weixinUrl=null, journalUrl=https://www.yxxb.com.cn/aps, iacademicId=null, status=1, seqNo=null, journalTitleEn=Acta Pharmaceutica Sinica, journalPhotoCn=BTxjudbJDVO4PqdBR6On6Q==, journalPhotoEn=c4l1ckL55nWbhl1KrFdWIA==, journalFirstLetter=Y, journalRecommend=null, journalNew=null, journalCollection=null, jcrJf=null, cjcrJf=null, jcrJfStr=null, cjcrJfStr=null, submissionFirstDecision=null, sciSubjectClassification=null, casSubjectClassification=null, citeScore=null, totalCitationFrequency=null, icpCode=null, psCode=null, advertisingLicenseCode=null, copyrightInformation=null, country=null, option=, provinceCode=null, provinceName=null, collectFlag=false, interPubPlatform=, interPubPlatformUrl=null), detailUrlCn=https://castjournals.cast.org.cn/joweb/yxxb/CN/10.16438/j.0513-4870.2025-0900, detailUrlEn=https://castjournals.cast.org.cn/joweb/yxxb/EN/10.16438/j.0513-4870.2025-0900, pdfUrlCn=https://castjournals.cast.org.cn/joweb/yxxb/CN/PDF/10.16438/j.0513-4870.2025-0900, pdfUrlEn=https://castjournals.cast.org.cn/joweb/yxxb/EN/PDF/10.16438/j.0513-4870.2025-0900, aliStartDate=0, aliEndDate=0, collectionFlag=false, citedCount=null, citedUrl=null, previewStatus=0, delFlag=0, hasFullText=1, orderTime=1765468800000, fullTextJson=null, articleText=null, reference=null)
收藏切换
共价抑制剂血浆蛋白结合特征的质谱分析技术研究进展
收藏切换
PDF下载
贤姝泽 , 王喆 , 许轩 , 徐晟源 , 生宁 , 张金兰 *
药学学报 | 综述 2025,60(12): 3692-3700
收起
收藏切换
药学学报 |综述 2025 , 60 (12) : 3692 -3700
共价抑制剂血浆蛋白结合特征的质谱分析技术研究进展
全屏
[Author(id=1308499676853273477, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, orderNo=0, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1308499676920382343, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, authorId=1308499676853273477, language=EN, stringName=Shu-ze XIAN, firstName=Shu-ze, middleName=null, lastName=XIAN, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1308499676983296904, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, authorId=1308499676853273477, language=CN, stringName=贤姝泽, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1308499676752610177, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, xref=null, ext=[AuthorCompanyExt(id=1308499676760998786, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, companyId=1308499676752610177, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1308499676773581699, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, companyId=1308499676752610177, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050)])]), Author(id=1308499677071377290, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, orderNo=1, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1308499677146874764, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, authorId=1308499677071377290, language=EN, stringName=Zhe WANG, firstName=Zhe, middleName=null, lastName=WANG, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1308499677205595021, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, authorId=1308499677071377290, language=CN, stringName=王喆, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1308499676752610177, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, xref=null, ext=[AuthorCompanyExt(id=1308499676760998786, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, companyId=1308499676752610177, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1308499676773581699, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, companyId=1308499676752610177, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050)])]), Author(id=1308499677260120975, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, orderNo=2, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1308499677331424145, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, authorId=1308499677260120975, language=EN, stringName=Xuan XU, firstName=Xuan, middleName=null, lastName=XU, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1308499677385950098, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, authorId=1308499677260120975, language=CN, stringName=许轩, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1308499676752610177, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, xref=null, ext=[AuthorCompanyExt(id=1308499676760998786, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, companyId=1308499676752610177, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1308499676773581699, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, companyId=1308499676752610177, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050)])]), Author(id=1308499677448864660, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, orderNo=3, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1308499677515973526, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, authorId=1308499677448864660, language=EN, stringName=Sheng-yuan XU, firstName=Sheng-yuan, middleName=null, lastName=XU, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1308499677583082391, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, authorId=1308499677448864660, language=CN, stringName=徐晟源, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1308499676752610177, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, xref=null, ext=[AuthorCompanyExt(id=1308499676760998786, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, companyId=1308499676752610177, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1308499676773581699, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, companyId=1308499676752610177, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050)])]), Author(id=1308499679252415385, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, orderNo=4, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1308499679365661595, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, authorId=1308499679252415385, language=EN, stringName=Ning SHENG, firstName=Ning, middleName=null, lastName=SHENG, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1308499679453741980, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, authorId=1308499679252415385, language=CN, stringName=生宁, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1308499676752610177, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, xref=null, ext=[AuthorCompanyExt(id=1308499676760998786, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, companyId=1308499676752610177, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1308499676773581699, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, companyId=1308499676752610177, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050)])]), Author(id=1308499679541822366, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, orderNo=5, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=zhjl@imm.ac.cn, emailSecond=null, emailThird=null, correspondingAuthor=1, authorType=1, ext={EN=AuthorExt(id=1308499679642485664, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, authorId=1308499679541822366, language=EN, stringName=Jin-lan ZHANG, firstName=Jin-lan, middleName=null, lastName=ZHANG, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=*, address=State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1308499679722177441, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, authorId=1308499679541822366, language=CN, stringName=张金兰, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=*, address=中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1308499676752610177, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, xref=null, ext=[AuthorCompanyExt(id=1308499676760998786, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, companyId=1308499676752610177, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1308499676773581699, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308468712672092341, companyId=1308499676752610177, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050)])])]
贤姝泽, 王喆, 许轩, 徐晟源, 生宁, 张金兰*
作者信息
  • 中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050
通讯作者:
张金兰, Tel: 86-10-50927323, Fax: 86-10-63017757, E-mail:
作者简介:

作者贡献:

贤姝泽完成文献调研、归纳分析和文章撰写; 许轩、徐晟源负责文献补充; 生宁负责理论指导和修改审校; 张金兰、王喆负责全程指导和修改审校。

Advances in mass spectrometry techniques for characterizing plasma protein binding of covalent inhibitors
Shu-ze XIAN, Zhe WANG, Xuan XU, Sheng-yuan XU, Ning SHENG, Jin-lan ZHANG*
Affiliations
  • State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
出版时间: 2025-12-12 doi: 10.16438/j.0513-4870.2025-0900
文章导航
收藏切换
摘要
收起

共价抑制剂通过与靶点形成共价键实现特异性结合, 可以在降低给药剂量的同时实现对靶点的长效抑制, 一定程度上攻克了传统难以成药的靶点, 在药物研发中展现出独特优势。共价抑制剂与血浆蛋白的结合特征与该类药物的药效、体内代谢特点以及毒副作用密切相关, 但目前对于该领域的研究还较为局限, 缺乏对不同弹头共价抑制剂与人血液中高丰度蛋白质结合的系统研究。同时, 质谱分析技术已经成为共价抑制剂与血浆蛋白结合特征研究的重要手段, 通过基于质谱的蛋白组学技术可以对共价抑制剂与血浆蛋白结合率、结合可逆性、结合影响因素、结合蛋白质种类及结合位点进行全面考察。本文对共价抑制剂的弹头、共价抑制剂与血浆蛋白结合特点及近年来质谱分析技术在共价抑制剂与血浆蛋白结合方面的研究进展进行综述, 为该类药物与血液中蛋白质结合研究提供参考。

血浆蛋白  /  质谱分析法  /  共价抑制剂  /  蛋白质组学  /  蛋白质结合

Covalent inhibitors can realize specific binding by forming covalent bonds with the target, which can realize long-lasting inhibition of the target while reducing the dosage, and to a certain extent, they have overcome the traditional targets that are difficult to become drugs, and they have shown unique advantages in drug discovery and development. The binding characteristics of covalent inhibitors to plasma proteins are closely related to the efficacy, in vivo metabolism, and toxic side effects of these drugs, but the current research in this field is still limited, and there is a lack of systematic studies on the binding of covalent inhibitors of different warheads to high abundance proteins in human blood. Meanwhile, mass spectrometry has become an important tool to characterize the binding of covalent inhibitors to plasma proteins, and mass spectrometry-based proteomics can be used to comprehensively investigate the binding rate, binding reversibility, binding influencing factors, binding protein species, and binding sites of covalent inhibitors to plasma proteins. In this paper, the warheads of covalent inhibitors, the binding characteristics of covalent inhibitors to blood proteins and the research progress of mass spectrometry in the binding of covalent inhibitors to plasma proteins in recent years are reviewed to provide a reference for the study of binding of this class of drugs to plasma proteins.

plasma protein  /  mass spectrometry  /  covalent inhibitor  /  proteomics  /  protein binding
贤姝泽, 王喆, 许轩, 徐晟源, 生宁, 张金兰. 共价抑制剂血浆蛋白结合特征的质谱分析技术研究进展. 药学学报, 2025 , 60 (12) : 3692 -3700 . DOI: 10.16438/j.0513-4870.2025-0900
Shu-ze XIAN, Zhe WANG, Xuan XU, Sheng-yuan XU, Ning SHENG, Jin-lan ZHANG. Advances in mass spectrometry techniques for characterizing plasma protein binding of covalent inhibitors[J]. Acta Pharmaceutica Sinica, 2025 , 60 (12) : 3692 -3700 . DOI: 10.16438/j.0513-4870.2025-0900
正文
收起
1　引言
收起
共价抑制剂是共价结合药物的重要类型, 被设计为能与特定分子靶点进行共价结合从而抑制其生物学功能的化合物[1], 也是近些年共价药物领域的研究热点。随着行业发展和技术进步, 共价抑制剂从偶然发现的时代转向合理设计和开发阶段, 已被用于攻克传统“不可成药”靶点。
共价抑制剂分为可逆共价抑制剂与不可逆共价抑制剂两种, 其与血浆蛋白的共价结合会影响血液中的游离药物浓度, 进而可能对药物的药代动力学行为、药效学特性以及安全性造成影响。共价抑制剂与血浆蛋白的共价结合会导致共价抑制剂在血液中更长的半衰期, 可逆的共价结合可以使药物在体内缓慢释放以达到更长效的药效, 而不可逆结合则可能导致药物难以释放、药效变差甚至造成毒性反应。研究共价抑制剂与血浆蛋白的结合可以明确药物在体内的存在形式与分布情况, 了解其对药物疗效、毒性的影响, 同时探究潜在的药物相互作用。因此, 需要对血液中蛋白质与共价抑制剂的结合开展研究, 本综述就近十年来共价抑制剂活性基团、血浆蛋白结合位点、结合研究技术进行了综述。
2　共价抑制剂的常见活性基团(弹头)
收起
已经有许多研究总结过常见的共价抑制剂弹头种类[2, 3], 根据相关研究及上市药物的数量, 本文将重点关注丙烯酰胺类、腈类、α, β-不饱和酮类、α-酮酰胺类、环硼酸及其酯类、β-内酰胺类及硼酸类几种弹头(图1)。
Kirsten大鼠肉瘤病毒癌基因同源物(Kirsten rat sarcoma viral oncogene homologue, KRAS) 与蛋白激酶均是传统非共价抑制剂难以成药的靶点, 也因此成为共价抑制剂的靶标热点。目前, 已有多种靶向蛋白激酶的共价抑制剂及靶向KRAS突变体KRASG12C的不可逆共价抑制剂阿达格拉西布(adagrasib) 和索托拉西布(sotorasib) 被批准上市。此外, 共价抑制剂的常见靶点还包括蛋白酶、结构蛋白、核转运蛋白、DNA及信号通路调控因子等。
共价抑制剂与其靶点的结合分为两个步骤: 首先是共价抑制剂通过非共价键与其生物靶标的可逆结合, 使配体上的活性基团接近靶蛋白上适当位置的亲核氨基酸残基; 第二步, 共价抑制剂的活性基团定位并结合在靶蛋白上的亲核氨基酸残基[1]。可逆共价抑制剂与其靶点共价结合后以比蛋白质周转速率更快的速度从靶标上解离; 而不可逆共价抑制剂与其靶点蛋白质形成的加合物, 可能在其靶点的生命周期内不发生解离, 也可能半衰期明显长于靶点蛋白质的再合成速率[1]。半胱氨酸(Cys) 是共价抑制剂最常见的结合位点, 美国食品药品监督管理局(Food and Drug Administration, FDA) 批准的共价抑制剂中有48%的药物能与Cys共价结合; 丝氨酸(Ser) 是仅次于Cys的第二大共价结合位点, β-内酰胺类弹头、环硼酸酯类弹头及部分α-酮酰胺类弹头均能与Ser共价结合; 其他能被共价抑制剂靶向的氨基酸残基还有苏氨酸(Thr)、赖氨酸(Lys) 等。尽管在各类弹头数据库(CovPDB、WHdb等) 中都有大量弹头可以与Lys共价结合, 但最终FDA批准上市的靶向Lys的共价抑制剂仅有一种, 即氨己烯酸, 这可能是因为Lys通常位于蛋白质表面, 其侧链在生理pH值下几乎完全质子化, 从而成为弱亲核试剂[2]。表1[4-6]总结了能与几种常见弹头结合的氨基酸及其反应类型。
由于共价抑制剂结构中除弹头外还有其他基团, 且其与血浆蛋白结合还会受到血浆蛋白结构及空间位阻的影响, 弹头与氨基酸的结合特征仅为共价抑制剂与血浆蛋白结合相关研究提供参考。
3　共价抑制剂与血液中蛋白质结合常见位点
收起
已经上市的共价抑制剂都是相对亲脂性的分子, 易与血清白蛋白(serum albumin, SA)、酸性糖蛋白(α1-acid glycoprotein, AAG)、球蛋白和各种脂蛋白等血浆蛋白及血红蛋白(hemoglobin, Hb) 产生共价结合[1]。表2[7-27]总结了2010年以来FDA批准上市的不同弹头共价抑制剂结合的常见血液蛋白及在蛋白上的氨基酸结合位点, 及已上市共价抑制剂的氨基酸靶点。
3.1　人血清白蛋白
人血清白蛋白(human serum albumin, HSA) 作为人血液中最丰富的蛋白质, 浓度约为630 μmol·L-1, 在血液中充当各种内源性和外源性化合物的载体[28], 也是血液中与共价抑制剂结合最多、最常见的靶蛋白。HSA包含三个结构上相同的结构域(Ⅰ、Ⅱ和Ⅲ), 每个结构域由两个亚结构域(A、B) 组成[8]。主要结合位点一个位于亚结构域ⅡA, 另一个位于亚结构域ⅢA, 分别称为Sudlow位点Ⅰ和Sudlow位点Ⅱ。最近发现了亚结构域IB (位点Ⅲ) 内的第三个结合口袋, 被认为是第三个主要结合位点[8]。目前可以检索到与血浆蛋白结合相关信息的共价抑制剂均会与HSA结合, 例如经典的β-内酰胺类弹头和丙烯酰胺类弹头的共价抑制剂头孢德考(cefiderocol)、伊布替尼(ibrutinib)、阿法替尼(afatinib)[7]以及新兴的α, β-不饱和酮类抑制剂和腈类弹头抑制剂富马酸二甲酯(dimethyl fumarate, DMF)[27]、奈玛特韦(nirmatrelvir)[24]等。
根据目前已有共价抑制剂-HSA结合位点研究, 最常报道的HSA与共价抑制剂结合位点是Lys, 如经典的布鲁顿酪氨酸激酶(Bruton's tyrosine kinase, BTK) 不可逆共价抑制剂伊布替尼与HSA的Lys106、137、351、414、525共价结合[10, 12]; 其次是Cys, 如DMF及其代谢物富马酸单甲酯(monomethyl fumarate, MMF) 在体外均与HSA的Cys34共价结合[27]。
尽管药物与HSA的体外结合相互作用已被认为是新药开发中研究药物与蛋白质结合行为的经典模型[28], 但通过对共价抑制剂与HSA结合研究文献检索与分析可以发现, 很多共价抑制剂的药物-HSA结合情况报道较少, 目前对共价抑制剂-HSA结合情况的研究重点还局限在对经典的丙烯酰胺弹头共价抑制剂的研究上。系统了解共价抑制剂与HSA的结合特点, 有助于更好地理解共价抑制剂在体内的吸收、分布、代谢、排泄(ADME) 行为。
3.2　 α1-酸性糖蛋白
人α1-酸性糖蛋白(human alpha1-acid glycoprotein, HAG) 是广泛存在于血液中一种分子质量44 kDa的酸转移蛋白, 是血浆中重要的急性期反应物[11], 由183个氨基酸残基组成, 但只有一个药物结合位点, 对碱性药物具有高亲和力[17]。HAG是仅次于HSA的、与共价抑制剂结合第二多的一种血浆蛋白, 但目前对共价抑制剂与HAG结合研究报道很少。已有研究发现某些共价抑制剂如腈弹头的Janus激酶共价抑制剂托法替尼(tofacitinib) 与HAG主要是通过疏水相互作用或氢键等非共价相互作用力进行结合的[23], 在进行药物-HAG结合相关研究时应该注意到这一点, 对药物与HAG结合进行更全面的分析。达康替尼(dacomitinib) 是一种高度选择性的第二代不可逆酪氨酸激酶抑制剂(tyrosine kinase inhibitor, TKI), Hu等[17]发现其通过C-H键与HAG的His97、Ile88、Arg90共价结合, 同时还通过氢键和疏水力等与HAG产生非共价结合, 是经典的同时通过共价与非共价作用与HAG结合的例子。
3.3　血红蛋白
人Hb是存在于红细胞中的金属蛋白, 负责将氧气从肺部运输到组织, 也是与药物结合的经典蛋白质之一。Hb的3D结构包含两条α链和两条β链, 它们分别由141个(由7个α螺旋组成) 和146个(由8个α螺旋组成) 氨基酸残基组成[29]。已有研究通过将共价抑制剂索托拉西布与大鼠全血样品共孵育后提取血浆蛋白和Hb并对其进行Bottom-up蛋白组学分析, 发现大鼠的SA和Hb是血液中与索托拉西布结合的主要蛋白质, 与SA的Lys549和Hb的Cys125、93、Lys82共价结合[30]。尽管已有研究发现了大鼠Hb与共价抑制剂的结合, 但对于人Hb与共价抑制剂结合情况的研究尚未见报道。一部分原因可能是因为之前的研究者们更倾向于用HSA或人血浆而非人全血或人Hb与共价抑制剂共孵育以进行共价抑制剂与蛋白结合情况的研究。
4　血浆蛋白结合率研究
收起
在进行共价抑制剂与血浆蛋白或血红蛋白共价结合的研究时, 超滤法和平衡透析法是常用的样品分离技术。样品经超滤法或平衡透析法分离后, 可以通过光谱法、高效色谱法或质谱法对血浆蛋白结合情况进行检测。
此外, 放射性同位素标记是进行共价抑制剂与血浆蛋白结合研究的重要技术手段。通过将放射性药物与全血/血浆共同孵育, 或给志愿者服用14C标记的共价抑制剂后采血[22], 对所得全血/血浆基质进行蛋白沉淀处理, 离心后通过液体闪烁计数器(liquid scintillation counter, LSC) 检测其上清液, 即可检测未与蛋白质结合的游离型放射性药物, 从而通过给药浓度和游离药物浓度计算共价抑制剂与血浆蛋白的结合率。或者将所得样品酶切后进样于与放射性检测器串联的超高效液相色谱/高效液相色谱(UPLC/HPLC-β-RAM) 中, 即可检测到共价抑制剂与蛋白质结合的放射性峰。通常, 将放射性药物-蛋白质结合物与PBS缓冲液共孵育以测定随时间变化释放出的游离药物的量是评价共价抑制剂与血浆蛋白结合可逆性的有效手段[10, 16, 22]。在孵育阶段改变孵育条件如孵育温度、孵育时间、缓冲液pH值和药物浓度等条件, 可以进一步考察药物-蛋白质结合可逆性的影响因素, 更好地理解在体内各种环境下的结合行为。
上述方法虽然操作简便且为研究者们广泛使用, 但只能判断药物与蛋白质是否结合及其结合率, 而难以得到其与蛋白质的结合位点及结合蛋白种类等信息。紫外-可见光谱(UV-Vis)、质谱(MS)、核磁共振(NMR)、圆二色光谱(CD)、荧光光谱法(FS)、分子对接以及分子动力学(MD) 模拟等技术可以进一步探索药物与血浆蛋白的结合及对结合氨基酸残基的表征。目前, MS技术成为常用的表征药物-蛋白质结合情况的技术手段。
5　血浆蛋白结合位点研究的质谱分析技术
收起
MS技术以及液相色谱-质谱联用(LC-MS) 技术可用于阐明共价抑制剂与血浆蛋白结合情况, 在已经报道的分析策略中, 基于MS的蛋白质组学技术是最常用的分析方法。
5.1　Top-down蛋白组学分析
Top-down蛋白组学分析是研究共价抑制剂结合蛋白质种类的常用技术, 通过高分辨质谱(HRMS) 分析未经酶切的完整蛋白质, 其经典的工作流程主要包括样品前处理、蛋白质分离、MS分析以及数据处理(图2)。
5.1.1　前处理
完整蛋白分析常见的前处理步骤是高丰度蛋白去除、蛋白质提取及除盐[31]。但对于共价抑制剂与血浆蛋白结合的研究, 由于其常与血液中的高丰度蛋白结合, 且这种结合比低丰度蛋白结合更具生理意义, 通常无需去除高丰度蛋白。蛋白质提取的常用试剂包括含除垢剂或离液剂等添加剂的缓冲液, 对于血浆样品, 通常无需进行提取处理[13]; 而对于红细胞样品, 可以采用氯化铵缓冲液、PBS缓冲液或Tris-HCl缓冲液等进行裂解, 根据实验需求考虑是否添加含十二烷基硫酸钠(sodium dodecyl sulfate, SDS) 或Triton X-100等添加剂增强裂解效率。
常见的除盐方法则包括膜超滤法(membrane ultrafiltration, MU)、氯仿-甲醇沉淀法(chloroform-methanol precipitation, CMP) 及固相萃取法(solid phase extraction, SPE) 等[32]。MU法利用特定截留分子量的半透膜截留大分子蛋白质, 离心或压力驱动使盐离子等小分子透过膜, 从而实现除盐与缓冲液置换。CMP是一种经典的在去污剂和脂质存在下从溶液中回收蛋白质的方法, 以蛋白质∶甲醇∶氯仿∶水= 1∶4∶3∶1的比例经涡旋、离心实现相分离。SPE则通过目标分析物和树脂之间的相互作用进行除盐, 通常包括三个步骤: 目标分析物与固体载体结合、污染物消除及目标分析物洗脱。
对Top-down的前处理方法进行优化有助于提高后续MS检测的灵敏度、降低检测所需样品量并缩短分析时间。Hossain等[31]开发了一种完整蛋白质LC-MS检测方法, 其在前处理时采用一种快速(约10 min) 的氯仿/乙醇分配技术, 该技术适用于多种生物基质, 且与LC-MS联用时获得高信噪比光谱所需的血量不到20 μL。
5.1.2　蛋白质分离方法
如前文所述, 对共价抑制剂-血浆蛋白结合的研究通常更关注血液中的高丰度蛋白, 因此在蛋白分离时通常无需使用多维分离技术。目前Top-down蛋白组学最常用的蛋白分离方法分别是液相色谱法(LC) 和电泳法。
目前常用的电泳分离方法包括凝胶电泳、毛细管电泳(CE)、毛细管电色谱(CEC) 和毛细管区间电泳(CZE) 等。其中, CZE因其灵敏度高且能够在天然条件下对蛋白质复合物进行高分辨率分离的特点成为推进大规模Top-down蛋白质组学的优势方法[33]。
除电泳法外, 分子排阻色谱法(SEC)、反相液相色谱法(RPLC) 等LC技术的发展也为蛋白质的分离提供了便利。而与这些传统流速液相色谱(300~1 000 μL·min-1) 相比, 低流速色谱如纳流色谱(nano-flow)、毛细管流色谱(micro-flow) 和微流色谱(capillary-flow) 具有流动相消耗量低、样品量小、灵敏度高的优势[34], 已被广泛应用于蛋白组学分析。
5.1.3　质谱分析
对基于MS的Top-down蛋白组学分析, 目前主要的蛋白质电离方法包括电喷雾电离(ESI) 和基质辅助激光解吸电离(MALDI)。其中, MALDI主要产生单电荷离子, 从而能够直接测定分子量。然而, 大多仪器对高质量单电荷离子的质量分辨率较低, 因此不足以分辨大分子蛋白质上的小质量数修饰。相比之下, ESI产生多电荷离子, 需要去卷积算法将信号从质荷比(m/z) 形式转换为分子量(Da) 形式, 但其可以与更高分辨率的质谱仪联用以产生足够的分辨率来检测大蛋白质上的微小质量变化[35]。
在完整蛋白分析中, 对MS原始数据进行去卷积以解析蛋白质的真实分子量是至关重要的步骤。Biopharma Finder (Thermo Fisher Scientific)、MassLynx™ (Waters Corporation)、OmniScape (Bruker) 等均是目前常用的数据分析软件。去卷积后可以将实测分子量与理论数据库进行比对, 通常可以根据不同仪器精度允许一定的质量误差, 直接匹配无修饰或已知修饰的蛋白质, 通过分子量差异推断未知修饰[10, 13]。莫博赛替尼(mobocertinib) 是一种用于治疗非小细胞肺癌(NSCLC) 的丙烯酰胺弹头抑制剂。Chen等[19]通过完整蛋白分析发现莫博赛替尼在人血浆内与HSA共价结合, 将莫博赛替尼与人血浆共孵育样品的MS结果解卷积, 可以检测到未结合的HSA (66 438 Da) 及与其相差一个莫博赛替尼分子质量(585 Da) 的HSA-伏美替尼结合物(67 023 Da)。
通过对完整蛋白质量的分析, 可以判断MS数据对应的蛋白种类及其是否与药物结合。而通过MS/MS的进一步碎裂, 可以对蛋白质进行全序列覆盖的鉴定[27]。尽管基于MS的Top-down蛋白组学分析已被证明在鉴定蛋白质修饰位点和确定多重修饰顺序方面具有一定优势, 但仍存在受蛋白质溶解性限制, 以及灵敏度相对较低等的技术挑战[36]。
5.2　Bottom-up蛋白组学分析
基于MS的Bottom-up蛋白质组学是研究共价抑制剂与蛋白质结合的一种很有优势的方法, 可以得到与共价抑制剂结合的蛋白质种类信息及结合的氨基酸位点信息(图3)。
5.2.1　前处理
在Bottom-up蛋白质组学研究中, 常见的前处理流程是变性、还原、烷基化、酶切、除盐后通过HPLC/UPLC-HRMS对肽段进行分离和检测[20]。对于血液样本, 需要用适量的缓冲液稀释以促进随后的酶切过程。常用的变性剂是尿素和硫脲, 可以破坏蛋白质的三维结构; 常用的还原剂是三(2-羧乙基)膦[tris(2-carboxyethyl)phosphine, TCEP] 或二硫苏糖醇(dithiothreitol, DTT); 常用的烷基化试剂则是碘乙酰胺(iodoacetamide, IAA), 能使还原形成的游离巯基烷基化, 以防止二硫键重组。在已有的共价抑制剂与蛋白质结合的研究中, 最常用的酶切方法是溶液内酶切(in-solution digestion, ISD) 和凝胶内酶切, 最常用的酶则是链霉蛋白酶或胰蛋白酶。其中, 胰蛋白酶∶蛋白质的比例通常在1∶20~1∶50, 其切割位点位于氨基酸残基Arg和Lys处, 可以获得800~2 000 Da的肽段, 适用于MS/MS测序[37]。
前处理是影响蛋白组学通量和重现性的关键因素。在前处理流程中, 酶切是影响共价抑制剂-蛋白质结合物定性及定量准确性和可重复性的关键步骤, 而ISD和凝胶内酶切的效率均较低, 可能对准确性及可重复性产生不利影响。基于此, 目前已有许多研究报道了改进整个前处理流程或其中某些步骤的新设备或新方法, 以缩短时间、提高通量并提高重现性, 如Chen等[38]开发的一种SISPROT (spintip-based proteomics technology) 装置, 集合了蛋白质预浓缩、还原、烷基化、酶切和高pH RP肽分离, 可以在标准离心机上进行多重分析, 且具有良好的重现性。但目前, 此类技术尚未发现被应用于研究共价抑制剂与血浆蛋白结合的领域。
5.2.2　肽段分离方法
在进行MS分析前, 酶切产生的肽混合物需要通过合适的分离方法使肽段与酶或其他化合物分离。
RPLC在肽混合物分离中起着关键作用。其他分离机制, 如强阳离子交换色谱(SCX)、强阴离子交换色谱(SAX)、SEC和亲水作用色谱(HILIC) 等常与RPLC联合使用, 以开发多维分离平台[37]。此外, 将具有不同分离机制的LC和CE技术联用还可以提高蛋白质检测的覆盖率, 适用于复杂蛋白质组的分析[39]。
5.2.3　质谱分析
Bottom-up蛋白组学是判断结合蛋白种类的优势方法, 通过分析物肽图相对血液中蛋白质序列的覆盖度, 可以判断与共价抑制剂结合的蛋白质种类。在进行Bottom-up蛋白组学分析时, 数据处理是解析与共价抑制剂结合的蛋白质种类及其结合位点的关键步骤。Uniprot是目前最常用的数据库。基于该数据库有多种数据分析平台, 如Proteome Discoverer (Thermo Fisher Scientific)、MaxQuant、Biopharma Finder (Thermo Fisher Scientific) 等。设置搜库参数时, 固定修饰通常设置为Cys的脲甲基化, 常见的可变修饰设置则包括Cys、Lys和Ser上共价抑制剂的修饰以及蛋白质N末端的乙酰化。设置搜库参数后, 将MS/MS数据导入相应的搜库软件进行搜库。目前常见的搜库原理是将通过MS获得的碎片离子与理论肽段进行匹配以确定实测的碎片离子所对应的肽段, 以此来判断共价抑制剂结合的蛋白质种类及其结合位点[27]。
伏美替尼(furmonertinib) 是一种用于治疗NSCLC的丙烯酰胺弹头TKI。Wu等[13]通过Bottom-up蛋白组学发现伏美替尼在人血浆内与HSA的肽段LKCASLQK、ASSAKQR共价结合, 通过碎片离子发现结合位点为Lys195和Lys199。
5.3　共价抑制剂-血浆蛋白结合物定量分析
靶向蛋白组学的平行反应监测技术(parallel reaction monitoring, PRM) 和多反应监测技术(multiple reaction monitoring, MRM) 已广泛应用于对药物-蛋白质结合物定量, 但目前在共价抑制剂和血浆蛋白结合的定量研究中应用较少。MRM通常使用三重四极杆质谱仪对肽段进行定量, 稳定性高且相对快速, 但分辨率较低[40]。奥希替尼(osimertinib) 是一种用于治疗NSCLC的不可逆TKI, 目前已有研究提出一种靶向奥希替尼-Cys结合物的MRM LC-MS/MS方法, 可以对包括血液在内的多种基质中的奥希替尼-蛋白质结合物进行定量[41]。而PRM与Top-down或Bottom-up策略结合, 可用于复杂生物样品中肽或蛋白质的准确定量, 与MRM相比分辨率和选择性更高, 但稳定性稍差。在研究中应依据实际需求对两种方法进行选择[40, 42]。
除检测方法外, 前处理方法对药物-蛋白质加合物的准确定量同样具有显著影响。若前处理方法选择不当, 可能增加除盐工作的难度甚至导致盐离子残留, 而SDS等表面活性剂的残留可能干扰质谱离子源的离子化效率, 导致检测信号抑制, 进而影响方法的准确性[43]。因此, 选择适当的添加剂和除盐方法对药物-蛋白质结合物的定量至关重要。Brown等[43]发现了一种非离子、可裂解的表面活性剂n-癸基二硫键-β-D-麦芽糖苷(n-decyl-disulfide-β-D-maltoside, DSSM), 有较好的细胞裂解效果且易于去除。此外, 由于Cys和Lys均为共价抑制剂的常见结合位点, 且Cys、Lys同时也分别是烷基化和胰蛋白酶酶切的位点, 因此烷基化与酶切均可能对药物-蛋白质结合物定量造成干扰。实验中可根据实际需求采用无烷基化前处理或替代酶进行酶切。
同时, 血液基质的复杂性也是影响药物-蛋白质结合物定量的关键因素。在前处理时必须选用恰当的方法除去样品中的脂质及内源性小分子, 避免基质效应对MS检测产生的干扰。此外, 样本的储存与处理条件也会对定量结果产生影响。例如, 全血样品保存不当(如抗凝剂选择错误或温度控制失当) 可诱发溶血, 导致红细胞内Hb释放至血浆基质中。由于Hb可能与血浆蛋白竞争性结合共价抑制剂, 若实验旨在模拟生理条件下蛋白与药物的结合状态, 此类溶血可能会对结合物的准确定量造成干扰。
6　总结与展望
收起
共价结合药物血浆蛋白结合特征的研究对于理解药物的药代动力学、药效学以及潜在的不良反应至关重要, 质谱分析技术在此领域已展现出独特优势与应用潜力。当前, 基于MS的Top-down和Bottom-up蛋白组学策略、超滤法及平衡透析法等研究方法已成功用于鉴定共价抑制剂-血浆蛋白形成加合物及结合位点, 为深入探究共价抑制剂-血浆蛋白相互作用机制提供了关键信息。然而, 目前对于共价抑制剂与血液中蛋白质结合的系统研究仍较为缺乏, 主要集中在对经典的共价丙烯酰胺弹头抑制剂的研究上, 对β-内酰胺弹头及腈类、硼酸及其酯类等新兴弹头共价抑制剂的血浆蛋白结合位点的研究较少。且目前对血浆蛋白的研究还主要局限于HSA, 对HAG及Hb等高丰度蛋白的研究仍较为匮乏。此外, 血液中其他常与药物产生结合的蛋白质如球蛋白和各种脂蛋白等血浆蛋白也尚未在共价抑制剂领域得到关注。
共价抑制剂与血浆蛋白结合相关的研究仍面临诸多挑战。一方面, 血浆基质的复杂性使蛋白组学的数据处理及搜库过程较为困难。另一方面, 现有质谱技术在定量分析共价结合药物与血浆蛋白结合率时, 仍面临前处理复杂, 准确性影响因素多等问题。总而言之, 了解共价抑制剂与血液中高丰度蛋白的结合情况有助于进一步理解共价抑制剂在体内的ADME过程及潜在的不良反应, 需要进一步的研究。

文献
收起
参考文献 引证文献
排序方式：
1
Baillie TA. Targeted covalent inhibitors for drug design [J]. Angew Chem Int Ed Engl, 2016, 55: 13408-13421.
2
Péczka N, Orgován Z, Ábrányi-Balogh P, et al. Electrophilic warheads in covalent drug discovery: an overview [J]. Expert Opin Drug Discov, 2022, 17: 413-422.
3
Dalton SE, Di Pietro O, Hennessy E. A medicinal chemistry perspective on FDA-approved small molecule drugs with a covalent mechanism of action [J]. J Med Chem, 2025, 68: 2307-2313.
4
Ou J, Zheng J, Huang J, et al. Interaction of acrylamide, acrolein, and 5-hydroxymethylfurfural with amino acids and DNA [J]. J Agric Food Chem, 2020, 68: 5039-5048.
5
Du H, Zhang X, Wu Z, et al. CovalentInDB 2.0: an updated comprehensive database for structure-based and ligand-based covalent inhibitor design and screening [J]. Nucleic Acids Res, 2025, 53: D1322-D1327.
6
Gao M, Moumbock AFA, Qaseem A, et al. CovPDB: a high-resolution coverage of the covalent protein-ligand interactome [J]. Nucleic Acids Res, 2021, 50: D445-D450.
7
Knox C, Wilson M, Klinger CM, et al. DrugBank 6.0: the DrugBank Knowledgebase for 2024 [J]. Nucleic Acids Res, 2024, 52: D1265-D1275.
8
Dömötör O, Pelivan K, Borics A, et al. Comparative studies on the human serum albumin binding of the clinically approved EGFR inhibitors gefitinib, erlotinib, afatinib, osimertinib and the investigational inhibitor KP2187 [J]. J Pharm Biomed Anal, 2018, 154: 321-331.
9
Wind S, Schnell D, Ebner T, et al. Clinical pharmacokinetics and pharmacodynamics of afatinib [J]. Clin Pharmacokinet, 2017, 56: 235-250.
10
Ballard TE, Dahal UP, Bessire AJ, et al. A tag-free collisionally induced fragmentation approach to detect drug-adducted proteins by mass spectrometry [J]. Rapid Commun Mass Spectrom, 2015, 29: 2175-2183.
11
Jiang SL, Li L, Hu L, et al. Comprehending binding features between ibrutinib and human alpha-1 acid glycoprotein: combined experimental approaches and theoretical simulations [J]. Spectrochim Acta A Mol Biomol Spectrosc, 2023, 285: 121834.
12
Muste C, Gu C. BTK-inhibitor drug covalent binding to lysine in human serum albumin using LC-MS/MS [J]. Drug Metab Pharmacokinet, 2022, 42: 100433.
13
Wu Y, Chen L, Chen J, et al. Covalent binding mechanism of furmonertinib and osimertinib with human serum albumin [J]. Drug Metab Dispos, 2023, 51: 8-16.
14
Kou Sb, Li L, Zhang RJ, et al. Elucidation of the interaction mechanism of olmutinib with human α-1 acid glycoprotein: insights from spectroscopic and molecular modeling studies [J]. J Biomol Struct Dyn, 2023, 41: 525-537.
15
Liu XY, Diao XX, Zhong DF. Advancements in the identification of adducts of drug-human serum albumin [J]. Acta Pharm Sin (药学学报), 2024, 59: 886-898.
16
Liu X, Feng D, Zheng M, et al. Characterization of covalent binding of tyrosine kinase inhibitors to plasma proteins [J]. Drug Metab Pharmacokinet, 2020, 35: 456-465.
17
Hu ZY, Sui HY, Zhong QF, et al. In vitro investigation of the binding characteristics of dacomitinib to human α1-acid glycoprotein: multispectral and computational modeling [J]. Spectrochim Acta A Mol Biomol Spectrosc, 2024, 314: 124197.
18
Vuu I, Dahal UP, Wang Z, et al. Absorption, metabolism and excretion of [14C]-sotorasib in healthy male subjects: characterization of metabolites and a minor albumin-sotorasib conjugate [J]. Cancer Chemother Pharmacol, 2022, 90: 357-367.
19
Chen H, Shah A, Kato S, et al. Metabolism and excretion of [14C]mobocertinib, a selective covalent inhibitor of epidermal growth factor receptor (EGFR) exon 20 insertion mutations, in healthy male subjects [J]. Drug Metab Dispos, 2024, 52: 1115-1123.
20
Dahal UP, Rock BM, Rodgers J, et al. Absorption, distribution, metabolism, and excretion of [14C]-sotorasib in rats and dogs: interspecies differences in absorption, protein conjugation and metabolism [J]. Drug Metab Dispos, 2022, 50: 600-612.
21
Rahbaek L, Cilliers C, Wegerski CJ, et al. Absorption, single-dose and steady-state metabolism, excretion, and pharmacokinetics of adagrasib, a KRASG12C inhibitor [J]. Cancer Chemother Pharmacol, 2024, 95: 7.
22
Meng J, Liu XY, Ma S, et al. Metabolism and disposition of pyrotinib in healthy male volunteers: covalent binding with human plasma protein [J]. Acta Pharmacol Sin, 2019, 40: 980-988.
23
Ajmal MR, Abdelhameed AS, Alam P, et al. Interaction of new kinase inhibitors cabozantinib and tofacitinib with human serum alpha-1 acid glycoprotein. A comprehensive spectroscopic and molecular docking approach [J]. Spectrochim Acta A Mol Biomol Spectrosc, 2016, 159: 199-208.
24
Greenfield SR, Eng H, Yang Q, et al. Species differences in plasma protein binding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease inhibitor nirmatrelvir [J]. Xenobiotica, 2023, 53: 12-24.
25
Griffith DC, Loutit JS, Morgan EE, et al. Phase 1 study of the safety, tolerability, and pharmacokinetics of the β-lactamase inhibitor vaborbactam (RPX7009) in healthy adult subjects [J]. Antimicrob Agents Chemother, 2016, 60: 6326-6332.
26
Al Jalali V, Wölfl-Duchek M, Taubert M, et al. Plasma and soft tissue pharmacokinetics of ceftolozane/tazobactam in healthy volunteers after single and multiple intravenous infusion: a microdialysis study [J]. J Antimicrob Chemother, 2021, 76: 2342-2351.
27
Xu L, Peng CC, Dawson K, et al. Metabolism, pharmacokinetics and excretion of [14C]dimethyl fumarate in healthy volunteers: an example of xenobiotic biotransformation following endogenous metabolic pathways [J]. Xenobiotica, 2023, 53: 163-172.
28
Abdelhameed AS, Alam P, Khan RH. Binding of Janus kinase inhibitor tofacitinib with human serum albumin: multi-technique approach [J]. J Biomol Struct Dyn, 2016, 34: 2037-2044.
29
Favinha AG, Barreiro DS, Martins JN, et al. Acrylamide-hemoglobin adduct: a spectroscopic study [J]. Spectrochim Acta A Mol Biomol Spectrosc, 2020, 241: 118644.
30
Gu TJ, Cai J, Auster A, et al. In vitro metabolism of targeted covalent inhibitors and their thiol conjugates by gut microbiome from rats, mice, and humans [J]. Drug Metab Dispos, 2025, 53: 100027.
31
Hossain MA, Brahme RR, Miller BC, et al. Mass spectrometry methods and mathematical PK/PD model for decision tree-guided covalent drug development [J]. Nat Commun, 2025, 16: 1777.
32
Sun LL, Liu XW. Membrane ultrafiltration-based sample preparation method and sheath-flow CZE-MS/MS for top-down proteomics [M] // Yang ZC, Sun LL. Methods in Molecular Biology. New York: Springer US, 2022: 5-14.
33
Shen X, Yang Z, Mccool EN, et al. Capillary zone electrophoresis-mass spectrometry for top-down proteomics [J]. Trends Analyt Chem, 2019, 120: 115644.
34
Shan L, Jones BR. Nano-LC: an updated review [J]. Biomed Chromatogr, 2022, 36: e5317.
35
Pu F, Ugrin SA, Radosevich AJ, et al. High-throughput intact protein analysis for drug discovery using infrared matrix-assisted laser desorption electrospray ionization mass spectrometry [J]. Anal Chem, 2022, 94: 13566-13574.
36
Tailor A, Waddington JC, Meng X, et al. Mass spectrometric and functional aspects of drug-protein conjugation [J]. Chem Res Toxicol, 2016, 29: 1912-1935.
37
Duong VA, Lee H. Bottom-up proteomics: advancements in sample preparation [J]. Int J Mol Sci, 2023, 24: 5350.
38
Chen W, Wang S, Adhikari S, et al. Simple and integrated spintip-based technology applied for deep proteome profiling [J]. Anal Chem, 2016, 88: 4864-4871.
39
Mikšík I. Coupling of CE-MS for protein and peptide analysis [J]. J Sep Sci, 2019, 42: 385-397.
40
Rozanova S, Barkovits K, Nikolov M, et al. Quantitative mass spectrometry-based proteomics: an overview [M] // Marcus K, Eisenacher M, Sitek B. Quantitative Methods in Proteomics. New York: Springer US, 2021: 85-116.
41
Gong S, Zhuo Y, Chen S, et al. Quantification of osimertinib and metabolite-protein modification reveals its high potency and long duration of effects on target organs [J]. Chem Res Toxicol, 2021, 34: 2309-2318.
42
Zhang L, Shen HL. Quantitative accuracy evaluation of mass spectrometry based proteomics methods commonly used in biomarker research [J]. Chem J Chin Univ (高等学校化学学报), 2024, 45: 203-211.
43
Brown KA, Gugger MK, Yu Z, et al. Nonionic, cleavable surfactant for top-down proteomics [J]. Anal Chem, 2023, 95: 1801-1804.
2025年第60卷第12期
PDF下载
192
93
引用本文
BibTeX
文章信息
doi: 10.16438/j.0513-4870.2025-0900
  • 接收时间：2025-08-01
  • 首发时间：2026-09-20
  • 出版时间：2025-12-12
补充材料
相关文章
文章信息
作者
出版历史
  • 收稿日期：2025-08-01
  • 修回日期：2025-09-25
基金
作者信息
    中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050

通讯作者:

张金兰, Tel: 86-10-50927323, Fax: 86-10-63017757, E-mail:
参考文献
分享链接
https://castjournals.cast.org.cn/joweb/yxxb/CN/10.16438/j.0513-4870.2025-0900
分享至
全文二维码

扫描看全文

引用本文
BibTeX
本文的引用情况
2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
关闭全屏
相关链接
论文
最新文章
热读文章
热点专题
内参
蓝皮书
产业发展报告
传播力报告
期刊分级目录
资讯
学术新闻
行业新闻
学术会议
行业会议
关于
关于我们
联系我们
北京市海淀区学院南路86号
100081
010-62662699（运营及技术支持）
qkjq@cast.org.cn

中国科学技术协会版权所有 京ICP 备10216604号-4 海淀分局备案 1101084647
科技导报社主办 中国科协信息中心技术支持