title: Human acidic mammalian chitinase as a novel target for anti-asthma drug design using in silico screening.
abstract: Human acidic mammalian chitinase (hAMCase) was recently shown to be involved in the development of asthma, suggesting a possible application for hAMCase inhibitors as novel therapeutic agents for asthma. We therefore initiated drug discovery research into hAMCase using a combination of in silico methodologies and a hAMCase assay system. We first selected 23 candidate hAMCase inhibitors from a database of four million compounds using a multistep screening system combining Tripos Topomer Search technology, a docking calculation and two-dimensional molecular similarity analysis. We then measured hAMCase inhibitory activity of the selected compounds and identified seven compounds with IC50 values ≤100 μM. A model describing the binding modes of these hit compounds to hAMCase was constructed, and we discuss the structure-activity relationships of the compounds we identified, suggested by the model and the actual inhibitory activities of the compounds.
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Wakasugi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Gouda
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Hirose
authors.forename: Akihiro
authors.initials: A
authors.lastname: Sugawara
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Kazuro
authors.initials: K
authors.lastname: Shiomi
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Sunazuka
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ōmura
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hirono
mesh_terms: D018927:Anti-Asthmatic Agents / Q000737:chemistry*; D001665:Binding Sites; D002688:Chitinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D003198:Computer Simulation; D062126:Databases, Chemical; D015195:Drug Design; D057166:High-Throughput Screening Assays; D006801:Humans; D062105:Molecular Docking Simulation; D010456:Peptides, Cyclic / Q000737:chemistry*; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D018927:Anti-Asthmatic Agents; D010456:Peptides, Cyclic; D011994:Recombinant Proteins; C413566:argifin; C499254:CHIA protein, human; D002688:Chitinases