title: A crystal structure-guided rational design switching non-carbohydrate inhibitors' specificity between two β-GlcNAcase homologs.
abstract: Selective inhibition of function-specific β-GlcNAcase has great potential in terms of drug design and biological research. The symmetrical bis-naphthalimide M-31850 was previously obtained by screening for specificity against human glycoconjugate-lytic β-GlcNAcase. Using protein-ligand co-crystallization and molecular docking, we designed an unsymmetrical dyad of naphthalimide and thiadiazole, Q2, that changes naphthalimide specificity from against a human glycoconjugate-lytic β-GlcNAcase to against insect and bacterial chitinolytic β-GlcNAcases. The crystallographic and in silico studies reveal that the naphthalimide ring can be utilized to bind different parts of these enzyme homologs, providing a new starting point to design specific inhibitors. Moreover, Q2-induced closure of the substrate binding pocket is the structural basis for its 13-fold increment in inhibitory potency. Q2 is the first non-carbohydrate inhibitor against chitinolytic β-GlcNAcases. This study provides a useful example of structure-based rationally designed inhibitors as potential pharmaceuticals or pesticides.
authors.affiliation: 1] School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, China [2].
authors.forename: Tian
authors.initials: T
authors.lastname: Liu
authors.affiliation: 1] Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China [2].
authors.forename: Peng
authors.initials: P
authors.lastname: Guo
authors.affiliation: 1] School of Software, Dalian University of Technology, Dalian 116620, China [2].
authors.forename: Yong
authors.initials: Y
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: School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: 1] Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China [2] State Key Laboratory of the Discovery and Development of Novel Pesticide, Shenyang Research Institute of Chemical Industry Co., Ltd, Shenyang 110021, China.
authors.forename: Huibin
authors.initials: H
authors.lastname: Yang
authors.affiliation: Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Xuhong
authors.initials: X
authors.lastname: Qian
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
mesh_terms: D000118:Acetylglucosaminidase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D019476:Insect Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D007700:Kinetics; D062105:Molecular Docking Simulation; D053644:Naphthalimides / Q000737:chemistry*; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D013830:Thiadiazoles / Q000737:chemistry*
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D019476:Insect Proteins; D053644:Naphthalimides; D013830:Thiadiazoles; D000118:Acetylglucosaminidase