Effective Virtual Screening Strategy toward Covalent Ligands: Identification of Novel NEDD8-Activating Enzyme Inhibitors

The NEDD8-activating enzyme (NAE) is an emerging target for cancer therapy, which regulates the degradation and turnover of a variety of cancer-related proteins by activating the cullin-RING E3 ubiquitin ligases. Among a limited number of known NAE inhibitors, the covalent inhibitors have demonstrated the most potent efficacy through their covalently linked adducts with NEDD8. Inspired by this unique mechanism, in this study, a novel combined strategy of virtual screening (VS) was adopted with the aim to identify diverse covalent inhibitors of NAE. To be specific, a docking-enabled pharmacophore model was first built from the possible active conformations of chosen covalent inhibitors. Meanwhile, a dynamic structure-based phamacophore was also established based on the snapshots derived from molecular dynamic simulation. Subsequent screening of a focused ZINC database using these pharmacophore models combined with covalent docking discovered three novel active compounds. Among them, compound LZ3 exhibited the most potent NAE inhibitory activity with an IC50 value of 1.06 ± 0.18 μM. Furthermore, a cell-based washout experiment proved the proposed covalent binding mechanism for compound LZ3, which confirmed the successful application of our combined VS strategy, indicating it may provide a viable solution to systematically discover novel covalent ligands.

• Publication year

  2014

• Venue

  Journal of Chemical Information and Modeling

• Publication date

  2014-06-12

• Fields of study

  Medicine, Chemistry, Computer Science

• Identifiers
  DOI 10.1021/ci5002058PMID 24857708
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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