6JJR

Crystal structure of human chitotriosidase-1 (hChit1) catalytic domain in complex with compound 2-8-14

Summary for 6JJR

• Entry DOI: 10.2210/pdb6jjr/pdb
• Descriptor: Chitotriosidase-1, 6-azanyl-2-oxidanylidene-N-[(1S)-1-phenylethyl]-7-(phenylmethyl)-1$l^{4},9-diaza-7-azoniatricyclo[8.4.0.0^{3,8}]tetradeca-1(14),3(8),4,6,10,12-hexaene-5-carboxamide (3 entities in total)
• Functional Keywords: chitinase, complex, chitotriosidase, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 43120.25

Authors

Jiang, X.,Yang, Q. (deposition date: 2019-02-26, release date: 2020-02-19, Last modification date: 2023-11-22)

Primary citation

Jiang, X.,Kumar, A.,Motomura, Y.,Liu, T.,Zhou, Y.,Moro, K.,Zhang, K.Y.J.,Yang, Q.
A Series of Compounds Bearing a Dipyrido-Pyrimidine Scaffold Acting as Novel Human and Insect Pest Chitinase Inhibitors.
J.Med.Chem., 63:987-1001, 2020

PubMed Abstract: Chitinases not only play vital roles in the human innate immune system but are also essential for the development of pathogenic fungi and pests. Chitinase inhibitors are efficient tools to investigate the elusive role of human chitinases and to control pathogens and pests. Via hierarchical virtual screening, we have discovered a series of chitinase inhibitors with a novel scaffold that have high inhibitory activities and selectivities against human and insect chitinases. The most potent human chitotriosidase inhibitor, compound , exhibited a of 49 nM, and the most potent inhibitor of the insect pest chitinase Chi-h, compound , exhibited a of 9 nM. The binding of these two most potent inhibitors was confirmed by X-ray crystallography. In a murine model of bleomycin-induced pulmonary fibrosis, compound was found to suppress the chitotriosidase activity by 60%, leading to a significant increase in inflammatory cells and suggesting that chitotriosidase played a protective role.

PubMed: 31928006
DOI: 10.1021/acs.jmedchem.9b01154

Experimental method

X-RAY DIFFRACTION (1.834 Å)