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.
Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China.
Hai-Jing
HJ
Zhong
Victor Pui-Yan
VP
Ma
Zhen
Z
Cheng
Daniel Shiu-Hin
DS
Chan
Hong-Zhang
HZ
He
Ka-Ho
KH
Leung
Dik-Lung
DL
Ma
Chung-Hang
CH
Leung
D001688:Biological Products / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018938:Caco-2 Cells; D019295:Computational Biology; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D044764:Ubiquitin-Activating Enzymes / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects*; D014584:User-Computer Interface
D001688:Biological Products; D004791:Enzyme Inhibitors; D044764:Ubiquitin-Activating Enzymes