期刊
BIOCHIMIE
卷 94, 期 11, 页码 2457-2460出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biochi.2012.06.004
关键词
Drug discovery; Virtual screening; Ubiquitin-like protein; NEDD8-activating enzyme; Natural product
资金
- Hong Kong Baptist University [FRG2/10-11/008, FRG2/11-12/009]
- Environment and Conservation Fund [3/2010]
- Centre for Cancer and Inflammation Research, School of Chinese Medicine (CCIR-SCM, HKBU)
- Research Fund for the Control of Infectious Diseases [RFCID/11101212]
- Research Grants Council [HKBU/201811]
- University of Macau [MYRG091(Y1-L2)-ICMS12-LCH, MYRG121(Y1-L2)-ICMS12-LCH]
NEDD8-activating enzyme (NAE) controls the specific degradation of proteins regulated by cullin-RING ubiquitin E3 ligase, and has been considered as an attractive molecular target for the development of anti-cancer drugs. We report herein the identification of the dipeptide-conjugated deoxyvasicinone derivative (1) as an inhibitor of NAE by virtual screening of over 90,000 compounds from the ZINC database of natural products. Molecular modelling results suggested that 1 may be a non-covalent competitive inhibitor of NAE by blocking the ATP-binding domain. Compound 1 was able to inhibit NAE activity in both cell-free and cell-based assay with potencies in the micromolar range and selectivity over analogous El enzymes UAE and SAE. We envisage that the identification and molecular docking analysis of this bioactive scaffold as an NAE inhibitor would provide the scientific community with useful information in order to generate more potent analogues. (C) 2012 Elsevier Masson SAS. All rights reserved.
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