Dynamics of Post-Translational Modification Inspires Drug Design in the Kinase Family

doi:10.1021/acs.jmedchem.1c01076

	Dynamics of Post-Translational Modification Inspires Drug Design in the Kinase Family
	Zhang, Huimin1,2,3,4 ; He, Jixiao 1; Hu, Guang 1; Zhu, Fei 1; Jiang, Hao2,3,4,5 ; Gao, Jing2,3,4,5 ; Zhou, Hu 2,3,4,5; Lin, Hua 6; Wang, Yingjuan 1; Chen, Kaixian2,3,4 ; Meng, Fanwang 7; Hao, Minghong 8; Zhao, Kehao 9; Luo, Cheng 2,3,4,5,10; Liang, Zhongjie 1
	2021
发表期刊	JOURNAL OF MEDICINAL CHEMISTRY (IF:6.8[JCR-2023],7.1[5-Year])
ISSN	0022-2623
EISSN	1520-4804
卷号	64 期号:20 页码:15111-15125
DOI	10.1021/acs.jmedchem.1c01076
摘要	Post-translational modification (PTM) on protein plays important roles in the regulation of cellular function and disease pathogenesis. The systematic analysis of PTM dynamics presents great opportunities to enlarge the target space by PTM allosteric regulation. Here, we presented a framework by integrating the sequence, structural topology, and particular dynamics features to characterize the functional context and druggabilities of PTMs in the well-known kinase family. The machine learning models with these biophysical features could successfully predict PTMs. On the other hand, PTMs were identified to be significantly enriched in the reported allosteric pockets and the allosteric potential of PTM pockets were thus proposed through these biophysical features. In the end, the covalent inhibitor DC-Srci-6668 targeting the PTM pocket in c-Src kinase was identified, which inhibited the phosphorylation and locked c-Src in the inactive state. Our findings represent a crucial step toward PTM-inspired drug design in the kinase family.
收录类别	SCIE
语种	英语
WOS研究方向	Pharmacology & Pharmacy
WOS类目	Chemistry, Medicinal
WOS记录号	WOS:000713412900013
出版者	AMER CHEMICAL SOC
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/131972
专题	生命科学与技术学院_博士生生命科学与技术学院_特聘教授组_陈凯先组物质科学与技术学院_外聘教师信息科学与技术学院_硕士生
通讯作者	Zhao, Kehao; Luo, Cheng; Liang, Zhongjie
作者单位	1.Soochow Univ, Ctr Syst Biol, Dept Bioinformat, Sch Biol & Basic Med Sci, Suzhou 215123, Peoples R China; 2.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 3.Chinese Acad Sci, Ctr Chem Biol, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 4.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China; 5.Univ Chinese Acad Sci UCAS, Beijing 100049, Peoples R China; 6.Fujian Normal Univ, Coll Life Sci, Biomed Res Ctr South China, Fuzhou 350117, Peoples R China; 7.McMaster Univ, Dept Chem & Chem Biol, Hamilton, ON L8S 4L8, Canada; 8.Ensem Therapeut Inc, Medford, MA 02155 USA; 9.Yantai Univ, Sch Pharm, Key Lab Mol Pharmacol & Drug Evaluat, Minist Educ,Collaborat Innovat Ctr Adv Drug Deliv, Yantai 264005, Peoples R China; 10.UCAS, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
第一作者单位	生命科学与技术学院
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Zhang, Huimin,He, Jixiao,Hu, Guang,et al. Dynamics of Post-Translational Modification Inspires Drug Design in the Kinase Family[J]. JOURNAL OF MEDICINAL CHEMISTRY,2021,64(20):15111-15125.
APA	Zhang, Huimin.,He, Jixiao.,Hu, Guang.,Zhu, Fei.,Jiang, Hao.,...&Liang, Zhongjie.(2021).Dynamics of Post-Translational Modification Inspires Drug Design in the Kinase Family.JOURNAL OF MEDICINAL CHEMISTRY,64(20),15111-15125.
MLA	Zhang, Huimin,et al."Dynamics of Post-Translational Modification Inspires Drug Design in the Kinase Family".JOURNAL OF MEDICINAL CHEMISTRY 64.20(2021):15111-15125.