Molecular modeling of human acidic mammalian chitinase in complex with the natural-product cyclopentapeptide chitinase inhibitor argifin

Hiroaki Gouda, Shinichi Terashima, Kanami Iguchi, Akihiro Sugawara, Yoshifumi Saito, Tsuyoshi Yamamoto, Tomoyasu Hirose, Kazuro Shiomi, Toshiaki Sunazuka, Satoshi Omura, Shuichi Hirono

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

Human acidic mammalian chitinase (hAMCase) is an attractive target for developing anti-asthma medications. We used a variety of computational methods to investigate the interaction between hAMCase and the natural-product cyclopentapeptide chitinase inhibitor argifin. The three-dimensional structure of hAMCase was first constructed using homology modeling. The interaction mode and binding free energy between argifin and hAMCase were then examined by the molecular-docking calculation and the molecular mechanics Poisson-Boltzmann surface area method combined with molecular dynamics simulation, respectively. The results suggested that argifin binds to hAMCase in a similar fashion to the interaction mode observed in the crystal structure of argifin-human chitotriosidase complex, and possesses inhibitory activity against hAMCase in the micromolar range. We further designed argifin derivatives expected to be selective for hAMCase.

Original languageEnglish
Pages (from-to)6270-6278
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume17
Issue number17
DOIs
Publication statusPublished - 2009 Sep 1
Externally publishedYes

Keywords

  • Binding free energy
  • Docking
  • In silico drug design
  • Molecular dynamics

ASJC Scopus subject areas

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

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