Abstract
Acidic mammalian chitinase (AMCase) is a potential target for inflammatory disorders, including Th2-driven diseases such as asthma, allergy, atopic dermatitis and allergic rhinitis. AMCase, along with human chitotriosidase (HCHT) are the two human chitinases that are enzymatically active. In this study, a comparative analysis of AMCase (PDB id. 3FY1) was done with that of HCHT (PDB id.1WAW) and Aspergillus fumigatus chitinase (PDB id.1W9U) to identify differences in the binding site topology and interacting residues. Argadin, a natural inhibitor of chitinases, was docked into the active site of AMCase. All the proteins have the DXDXE motif, like other family 18 chitinases. There is a crucial difference in the stacking interactions in chitinases. The chitinase of Aspergillus fumigatus (AfchiB1) is unique in having Phe251 compared to Trp in others at the same position. Arg269 forms strong hydrogen bonds with argadin in HCHT and AfchiB1 but not in AMCase. Many crucial differences between the binding sites of AMCase and HCHT were identified. As AMCase has aroused considerable interest as the major target for the discovery of anti-asthma agents, these differences at the binding site of AMCase may be exploited for selective inhibitor design. The binding affinities, determined based on energy minimization studies, suggest a lower affinity of argadin for AMCase when compared to that for HCHT and AfchiB1.
Keywords: Asthma, Acidic mammalian chitinase, Argadin, Chitotriosidase, Molecular mechanics calculations
5