title: A Novel Scaffold for Developing Specific or Broad-Spectrum Chitinase Inhibitors.
abstract: Chitinases play important roles in pathogen invasion, arthropod molting, plant defense, and human inflammation. Inhibition of the activity of a typical chitinase by small molecules is of significance in drug development and biological research. On the basis of a recent reported crystal structure of OfChtI, the insect chitinase derived from the pest Ostrinia furnacalis, we computationally identified 17 compounds from a library of over 4 million chemicals by two rounds virtual screening. Among these, three compounds from one chemical class inhibited the activity of OfChtI with single-digit-micromolar IC50values, and one compound from another chemical class exhibited a broad inhibitory activity not only toward OfChtI but also toward bacterial, fungal, and human chitinases. A new scaffold was discovered, and a structure-inhibitory activity relationship was proposed. This work may provide a novel starting point for the development of specific or broad-spectrum chitinase inhibitors.
authors.affiliation: State Key Laboratory of Fine Chemicals and School of Life Science and Biotechnology, Dalian University of Technology , No. 2 Linggong Road, Dalian 116024, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Structural Bioinformatics Team, Center for Life Science Technologies, RIKEN , 1-7-22 Suehiro, Tsurumi, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Kumar
authors.affiliation: State Key Laboratory of Fine Chemicals and School of Life Science and Biotechnology, Dalian University of Technology , No. 2 Linggong Road, Dalian 116024, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Liu
authors.affiliation: Structural Bioinformatics Team, Center for Life Science Technologies, RIKEN , 1-7-22 Suehiro, Tsurumi, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Kam Y J
authors.initials: KY
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Fine Chemicals and School of Life Science and Biotechnology, Dalian University of Technology , No. 2 Linggong Road, Dalian 116024, China.|Institute of Plant Protection, Chinese Academy of Agricultural Sciences , Beijing 100193, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
mesh_terms: D000818:Animals; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology; D002688:Chitinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005658:Fungi / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007306:Insecticides / Q000737:chemistry* / Q000494:pharmacology*; D007915:Lepidoptera / Q000187:drug effects / Q000201:enzymology*; D062105:Molecular Docking Simulation; D010571:Pest Control; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007306:Insecticides; D002688:Chitinases