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

Abstract Human acidic mammalian chitinase ( h AMCase) is an attractive target for developing anti-asthma medications. We used a variety of computational methods to investigate the interaction between h AMCase and the natural-product cyclopentapeptide chitinase inhibitor argifin. The three-dimensional structure of h AMCase was first constructed using homology modeling. The interaction mode and binding free energy between argifin and h AMCase 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 h AMCase in a similar fashion to the interaction mode observed in the crystal structure of argifin-human chitotriosidase complex, and possesses inhibitory activity against h AMCase in the micromolar range. We further designed argifin derivatives expected to be selective for h AMCase.