Crystal Structure and Structure-Based Discovery of Inhibitors of the Nematode Chitinase CeCht1.

Nematode chitinases play crucial roles in various processes of the nematode lifecycle, including hatching, molting, and reproduction. Small-molecule inhibitors of nematode chitinases have shown promise for controlling nematode pests. However, the lack of structural information makes it a challenge to develop nematicides targeting nematode chitinases. Here, we report the first crystal structure of a representative nematode chitinase, that of CeCht1 from the model nematode Caenorhabditis elegans, to a 1.7 Å resolution. CeCht1 is a highly conserved chitinase among nematodes, and structural comparison with other chitinases revealed that CeCht1 has a classical TIM-barrel fold with some subtle structural differences in the substrate-binding cleft. Benefiting from the obtained crystal structure, we identified a series of novel inhibitors by hierarchical virtual screening. Analysis of the structure-activity relationships of these compounds provided insight into their interactions with the enzyme active site, which may inform future work in improving the potencies of their inhibitory activities. This work gives an insight into the structural features of nematode chitinases and provides a solid basis for the development of inhibitors.