Discovery of a natural product inhibitor targeting protein neddylation by structure-based virtual screening

Hai Jing Zhong, Victor Pui-Yan Ma, Zhen Cheng, Daniel Shiu-Hin Chan, Hong Zhang He, Ka Ho Leung, Edmond Dik Lung MA, Chung Hang Leung*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

49 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2457-2460
Number of pages4
JournalBiochimie
Volume94
Issue number11
DOIs
Publication statusPublished - Nov 2012

Scopus Subject Areas

  • Biochemistry

User-Defined Keywords

  • Drug discovery
  • Natural product
  • NEDD8-activating enzyme
  • Ubiquitin-like protein
  • Virtual screening

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