Molecular modeling of human acidic mammalian chitinase in complex with the natural-product cyclopentapeptide chitinase inhibitor argifin.
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.
Gouda
Hiroaki
H
School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. godah@pharm.kitasato-u.ac.jp
Terashima
Shinichi
S
Iguchi
Kanami
K
Sugawara
Akihiro
A
Saito
Yoshifumi
Y
Yamamoto
Tsuyoshi
T
Hirose
Tomoyasu
T
Shiomi
Kazuro
K
Sunazuka
Toshiaki
T
Omura
Satoshi
S
Hirono
Shuichi
S
D000595:Amino Acid Sequence; D018927:Anti-Asthmatic Agents / Q000737:chemistry* / Q000494:pharmacology; D002688:Chitinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003198:Computer Simulation; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008956:Models, Chemical; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013816:Thermodynamics
D018927:Anti-Asthmatic Agents; D004791:Enzyme Inhibitors; D010456:Peptides, Cyclic; C413566:argifin; D002688:Chitinases