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

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• 作者：Shengping Zhang ; Jiani Tan ; Zhonghui Lai ; Ying Li ; Junxia Pang ; Jianhu Xiao ; Zhangjian Huang ; Yihua Zhang ; Hui Ji ; Yisheng Lai
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2014
• 出版时间：June 23, 2014
• 年：2014
• 卷：54
• 期：6
• 页码：1785-1797
• 全文大小：626K
• ISSN：1549-960X

文摘

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 卤 0.18 渭M. 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.