Human acidic mammalian chitinase as a novel target for anti-asthma drug design using in silico screening

Masaki Wakasugi, Hiroaki Gouda, Tomoyasu Hirose, Akihiro Sugawara, Tsuyoshi Yamamoto, Kazuro Shiomi, Toshiaki Sunazuka, Satoshi Omura, Shuichi Hirono

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3214-3220
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number11
DOIs
Publication statusPublished - 2013 Jun 1
Externally publishedYes

Keywords

  • Asthma medications
  • Chitinase
  • In silico screening
  • Inhibitor
  • Structure-based drug design

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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