title: Structure-based repurposing of FDA-approved drugs as inhibitors of NEDD8-activating enzyme.
abstract: We report the discovery of an inhibitor of NEDD8-activating enzyme (NAE) by an integrated virtual screening approach. Piperacillin 1 inhibited NAE activity in cell-free and cell-based systems with high selectivity. Furthermore, piperacillin 1 was able to inhibit the degradation of the NAE downstream protein substrate p27(kip1). Our molecular modeling and kinetic studies suggested that this compound may act as a non-covalent ATP-competitive inhibitor of NAE.
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Hai-Jing
authors.initials: HJ
authors.lastname: Zhong
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Liu
authors.affiliation: Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.
authors.forename: Daniel Shiu-Hin
authors.initials: DS
authors.lastname: Chan
authors.affiliation: Department of Fragrance and Cosmetic Science, Graduate Institute of Natural Products, Kaohsiung Medical University, Taiwan, ROC.
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Wang
authors.affiliation: Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore.
authors.forename: Philip Wai Hong
authors.initials: PW
authors.lastname: Chan
authors.affiliation: Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China. Electronic address: edmondma@hkbu.edu.hk.
authors.forename: Dik-Lung
authors.initials: DL
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China. Electronic address: duncanleung@umac.mo.
authors.forename: Chung-Hang
authors.initials: CH
authors.lastname: Leung
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D003517:Cyclopentanes / Q000737:chemistry* / Q000627:therapeutic use; D017277:Drug Approval; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000302:isolation & purification / Q000627:therapeutic use; D006801:Humans; D011743:Pyrimidines / Q000737:chemistry* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D044764:Ubiquitin-Activating Enzymes / Q000037:antagonists & inhibitors / Q000737:chemistry*; D014481:United States; D014486:United States Food and Drug Administration; D014584:User-Computer Interface
chemical_list: D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D000255:Adenosine Triphosphate; D044764:Ubiquitin-Activating Enzymes; C491802:NAE protein, human; C539933:pevonedistat
keywords: Inhibitor; NEDD8-activating enzyme; Repurposing; Structure-based; Virtual screening