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Discovery of deoxyvasicinone derivatives as inhibitors of NEDD8-activating enzyme
Zhong H.-J.1; Leung K.-H.2; Lin S.2; Chan D.S.-H.2; Han Q.-B.3; Chan S.L.-F.4; Ma D.-L.2; Leung C.-H.1
2015
Source PublicationMethods
ISSN10959130 10462023
Volume71Issue:CPages:71-76
Abstract

NEDD8-activating enzyme (NAE) controls the specific degradation of proteins regulated by cullin-RING ubiquitin E3 ligases, and has been considered as an attractive molecular target for the development of drugs against cancer. A pharmacophore model constructed from a training set of deoxyvasicinone derivatives was used to screen 376 compounds from an analogue database. From the initial screening, the valine-linked deoxyvasicinone derivative 9 and the N-isopropyl-linked deoxyvasicinone derivative 10 emerged as the top scoring candidates. Compounds 9 and 10 showed micromolar potencies in both cell-free and cell-based systems, with selectivity for NAE over the related enzymes SAE and UAE. Molecular modelling analysis suggested that 9 and 10 may inhibit NAE by blocking the ATP-binding domain. Thus, these deoxyvasicinone derivatives could be considered as promising lead molecules for the development of more potent inhibitors of NAE.

KeywordDeoxyvasicinone Drug Discovery Nedd8 Pharmacophore Ubiquitin-like
DOI10.1016/j.ymeth.2014.08.014
URLView the original
Indexed BySCIE
Language英语
WOS Research AreaBiochemistry & Molecular Biology
WOS SubjectBiochemical Research Methods ; Biochemistry & Molecular Biology
WOS IDWOS:000348264200010
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Cited Times [WOS]:11   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Corresponding AuthorMa D.-L.; Leung C.-H.
Affiliation1.State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
2.Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong
3.School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon Tong, Hong Kong
4.Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong
First Author AffilicationInstitute of Chinese Medical Sciences
Corresponding Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Zhong H.-J.,Leung K.-H.,Lin S.,et al. Discovery of deoxyvasicinone derivatives as inhibitors of NEDD8-activating enzyme[J]. Methods,2015,71(C):71-76.
APA Zhong H.-J..,Leung K.-H..,Lin S..,Chan D.S.-H..,Han Q.-B..,...&Leung C.-H..(2015).Discovery of deoxyvasicinone derivatives as inhibitors of NEDD8-activating enzyme.Methods,71(C),71-76.
MLA Zhong H.-J.,et al."Discovery of deoxyvasicinone derivatives as inhibitors of NEDD8-activating enzyme".Methods 71.C(2015):71-76.
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