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, Huimin 2,3,4,5; He, Jixiao 2; Hu, Guang 2; Zhu, Fei 2; Jiang, Hao 3,4,5,6; Gao, Jing 3,4,5,6; Zhou, Hu 3,4,5,6; Lin, Hua 7; Wang, Yingjuan 2; Chen, Kaixian 3,4,5
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2021-10-28
卷号	64 期号:20 页码:15111-15125
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.1c01076
通讯作者	Zhao, Kehao(kehaozhao@gmail.com) ; Luo, Cheng(cluo@simm.ac.cn) ; Liang, Zhongjie(zjliang@suda.edu.cn)
英文摘要	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.
资助项目	National Natural Science Foundation of China[91853205] ; National Natural Science Foundation of China[81821005] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[81728020] ; National Natural Science Foundation of China[31872723] ; Key Laboratory of Systems Biomedicine (Ministry of Education) ; Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University[KLSB2019KF-02] ; Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions ; Science and Technology Commission of Shanghai Municipality[19XD1404700] ; Science and Technology Commission of Shanghai Municipality[18431907100] ; Top Talents Program for One Discussion of Shandong Province
WOS关键词	C-SRC KINASE ; 3-DIMENSIONAL STRUCTURES ; ACTIVE CONFORMATION ; BINDING SITES ; PHOSPHORYLATION ; ACTIVATION ; INHIBITORS ; DATABASE ; PHOSPHO3D ; CANCER
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000713412900013
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/298991]
专题	中国科学院上海药物研究所
通讯作者	Zhao, Kehao; Luo, Cheng; Liang, Zhongjie
作者单位	1.UCAS, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 2.Soochow Univ, Ctr Syst Biol, Dept Bioinformat, Sch Biol & Basic Med Sci, Suzhou 215123, Peoples R China 3.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 4.Chinese Acad Sci, Ctr Chem Biol, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 5.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 6.Univ Chinese Acad Sci UCAS, Beijing 100049, Peoples R China 7.Fujian Normal Univ, Coll Life Sci, Biomed Res Ctr South China, Fuzhou 350117, Peoples R China 8.McMaster Univ, Dept Chem & Chem Biol, Hamilton, ON L8S 4L8, Canada 9.Ensem Therapeut Inc, Medford, MA 02155 USA 10.Yantai Univ, Sch Pharm, Key Lab Mol Pharmacol & Drug Evaluat, Minist Educ,Collaborat Innovat Ctr Adv Drug Deliv, Yantai 264005, Peoples R China
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.