Determining Cysteines Available for Covalent Inhibition Across the Human Kinome

doi:10.1021/acs.jmedchem.6b01815

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	Determining Cysteines Available for Covalent Inhibition Across the Human Kinome
	Zhao, Zheng 1; Liu, Qingsong 2; Bliven, Spencer 1,3; Xie, Lei 4,5; Bourne, Philip E.1,6
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2017-04-13
卷号	60 期号:7 页码:2879-2889
DOI	10.1021/acs.jmedchem.6b01815
文献子类	Article
英文摘要	Covalently bound protein kinase inhibitors have been frequently designed to target noncatalytic cysteines at the ATP binding site. Thus, it is important to know if a given cysteine can form a covalent bond. Here we combine a function-site interaction fingerprint method and DFT calculations to determine the potential of cysteines to form a covalent interaction with an inhibitor. By harnessing the human structural kinome, a comprehensive structure-based binding site cysteine data set was assembled. The orientation of the cysteine thiol group indicates which cysteines can potentially form covalent bonds. These covalent inhibitor easy available cysteines are located within five regions: P-loop, roof of pocket, front pocket, catalytic-2 of the catalytic loop, and DFG-3 close to the DFG peptide. In an independent test set these cysteines covered 95% of covalent kinase inhibitors. This study provides new insights into cysteine reactivity and preference which is important for the prospective development of covalent kinase inhibitors.
WOS关键词	TRANSITION-STATE CALCULATIONS ; KINASE INHIBITORS ; MICHAEL ADDITION ; TYROSINE KINASE ; DRUG DISCOVERY ; IRREVERSIBLE INHIBITORS ; ACCEPTOR REACTIVITY ; PSEUDOKINASE HER3 ; PROTEIN-KINASES ; LUNG-CANCER
WOS研究方向	Pharmacology & Pharmacy
语种	英语
WOS记录号	WOS:000399436100018
资助机构	Intramural Research Program of the National Library of Medicine, National Institutes of Health ; Intramural Research Program of the National Library of Medicine, National Institutes of Health ; Intramural Research Program of the National Library of Medicine, National Institutes of Health ; Intramural Research Program of the National Library of Medicine, National Institutes of Health ; Intramural Research Program of the National Library of Medicine, National Institutes of Health ; Intramural Research Program of the National Library of Medicine, National Institutes of Health ; Intramural Research Program of the National Library of Medicine, National Institutes of Health ; Intramural Research Program of the National Library of Medicine, National Institutes of Health ; Intramural Research Program of the National Library of Medicine, National Institutes of Health ; Intramural Research Program of the National Library of Medicine, National Institutes of Health ; Intramural Research Program of the National Library of Medicine, National Institutes of Health ; 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National Institute on Minority Health and Health Disparities, National Institutes of Health(G12MD007599) ; National Institute on Minority Health and Health Disparities, National Institutes of Health(G12MD007599) ; Intramural Research Program of the National Library of Medicine, National Institutes of Health ; Intramural Research Program of the National Library of Medicine, National Institutes of Health ; Intramural Research Program of the National Library of Medicine, National Institutes of Health ; Intramural Research Program of the National Library of Medicine, National Institutes of Health ; Intramural Research Program of the National Library of Medicine, National Institutes of Health ; Intramural Research Program of the National Library of Medicine, National Institutes of Health ; Intramural Research Program of the National Library of Medicine, National Institutes of Health ; Intramural Research Program of the National Library of Medicine, National Institutes of Health ; Intramural Research Program of the National Library of Medicine, National Institutes of Health ; 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National Institute on Minority Health and Health Disparities, National Institutes of Health(G12MD007599) ; National Institute on Minority Health and Health Disparities, National Institutes of Health(G12MD007599) ; National Institute on Minority Health and Health Disparities, National Institutes of Health(G12MD007599) ; National Institute on Minority Health and Health Disparities, National Institutes of Health(G12MD007599) ; National Institute on Minority Health and Health Disparities, National Institutes of Health(G12MD007599) ; National Institute on Minority Health and Health Disparities, National Institutes of Health(G12MD007599) ; National Institute on Minority Health and Health Disparities, National Institutes of Health(G12MD007599) ; National Institute on Minority Health and Health Disparities, National Institutes of Health(G12MD007599) ; National Institute on Minority Health and Health Disparities, National Institutes of Health(G12MD007599) ; National Institute on Minority Health and Health Disparities, National Institutes of Health(G12MD007599) ; National Institute on Minority Health and Health Disparities, National Institutes of Health(G12MD007599) ; National Institute on Minority Health and Health Disparities, National Institutes of Health(G12MD007599) ; National Institute on Minority Health and Health Disparities, National Institutes of Health(G12MD007599) ; National Institute on Minority Health and Health Disparities, National Institutes of Health(G12MD007599)
内容类型	期刊论文
源URL	[http://ir.hfcas.ac.cn:8080/handle/334002/33378]
专题	合肥物质科学研究院_中科院强磁场科学中心
作者单位	1.Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20892 USA 2.Chinese Acad Sci, High Field Magnet Lab, Hefei 230031, Anhui, Peoples R China 3.Paul Scherrer Inst, Lab Biomol Res, CH-5232 Villigen, Switzerland 4.CUNY, Hunter Coll, Dept Comp Sci, New York, NY 10065 USA 5.CUNY, Grad Ctr, New York, NY 10016 USA 6.NIH, Off Director, Bldg 10, Bethesda, MD 20892 USA
推荐引用方式 GB/T 7714	Zhao, Zheng,Liu, Qingsong,Bliven, Spencer,et al. Determining Cysteines Available for Covalent Inhibition Across the Human Kinome[J]. JOURNAL OF MEDICINAL CHEMISTRY,2017,60(7):2879-2889.
APA	Zhao, Zheng,Liu, Qingsong,Bliven, Spencer,Xie, Lei,&Bourne, Philip E..(2017).Determining Cysteines Available for Covalent Inhibition Across the Human Kinome.JOURNAL OF MEDICINAL CHEMISTRY,60(7),2879-2889.
MLA	Zhao, Zheng,et al."Determining Cysteines Available for Covalent Inhibition Across the Human Kinome".JOURNAL OF MEDICINAL CHEMISTRY 60.7(2017):2879-2889.