title: Exploring NAG-thiazoline and its derivatives as inhibitors of chitinolytic β-acetylglucosaminidases.
abstract: NAG-thiazoline (NGT) and its derivatives are well-known inhibitors against most β-acetylglucosaminidases (β-GlcNAcases) except for insect and bacterial chitinolytic β-GlcNAcases, including the molting-indispensable OfHex1 from the insect Ostrinia furnacalis. Here, we report the co-crystal structure of OfHex1 in complex with NGT. This structure reveals a large active pocket in OfHex1 that may account for the poor inhibitory activity of NGT. To test this hypothesis, a bulky substituent was designed and synthesized on the thiazoline ring of NGT. The resulting compound (NMAGT) was determined to be a submicromolar inhibitor of OfHex1 with a Ki value of 0.13 μM, which is 600-fold lower than Ki value of NGT. Molecular dynamics simulation analysis supported the good fit of NMAGT to the active pocket.
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Liu
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Xia
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200237, China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Industrial Ecology and Environmental Engineering, School of Food and Environmental Science and Technology, Dalian University of Technology, Panjin 124000, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhou
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200237, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, China. Electronic address: qingyang@dlut.edu.cn.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
mesh_terms: D000117:Acetylglucosamine / Q000031:analogs & derivatives* / Q000737:chemistry; D000118:Acetylglucosaminidase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry*; D019476:Insect Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D009036:Moths / Q000201:enzymology*; D013844:Thiazoles / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D019476:Insect Proteins; D013844:Thiazoles; D000118:Acetylglucosaminidase; C487818:N-acetylglucosamine thiazoline; D000117:Acetylglucosamine
keywords: Chitinolytic enzyme; Inhibitor; NGT; β-Acetylglucosaminidase