Department of Chemistry
Discovery of a natural product inhibitor targeting protein neddylation by structure-based virtual screening
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 E1 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. © 2012 Elsevier Masson SAS. All rights reserved.
Drug discovery, Natural product, NEDD8-activating enzyme, Ubiquitin-like protein, Virtual screening
Source Publication Title
Zhong, Hai-Jing, Victor Pui-Yan Ma, Zhen Cheng, Daniel Shiu-Hin Chan, Hong-Zhang He, Ka-Ho Leung, Dik-Lung Ma, and Chung-Hang Leung. "Discovery of a natural product inhibitor targeting protein neddylation by structure-based virtual screening." Biochimie 94.11 (2012): 2457-2460.