A Novel Scaffold for Developing Specific or Broad-Spectrum Chitinase Inhibitors

Abstract

Chitinases play important roles in pathogen invasion, arthropod molting, plant defense, and human inflammation. Inhibition of the activity of a typical chitinase by small molecules is of significance in drug development and biological research. On the basis of a recent reported crystal structure of OfChtI, the insect chitinase derived from the pest Ostrinia furnacalis, we computationally identified 17 compounds from a library of over 4 million chemicals by two rounds virtual screening. Among these, three compounds from one chemical class inhibited the activity of OfChtI with single-digit-micromolar IC values, and one compound from another chemical class exhibited a broad inhibitory activity not only toward OfChtI but also toward bacterial, fungal, and human chitinases. A new scaffold was discovered, and a structure-inhibitory activity relationship was proposed. This work may provide a novel starting point for the development of specific or broad-spectrum chitinase inhibitors.

Glycoside hydrolase family 18 and 20 enzymes are novel targets of the traditional medicine berberine

“…The catalytic domains of OfChtI from O. furnacalis, human HsCht, and human AMCase were expressed in P. pastoris GS115 and purified as described previously (39,53,54). HsOGA was expressed in Escherichia coli and purified as described previously (40).…”

“…In the previous work, we noticed that compounds with a large conjugated plane were highly potent inhibitors of GH20 Hex (21,42) and GH18 chitinase (39). Berberine is a typical compound with a large conjugated plane.…”

Structure-based virtual screening of highly potent inhibitors of the nematode chitinase CeCht1

“…A hierarchical virtual screening strategy was used as described previously 13 , 27 , 29 . First, structural analogues to active hits were identified from a subset of commercially available compounds from ZINC database 30 employing substructure search and shape similarity calculations.…”

“…The scarce nematode chitinase inhibitors may be, to a great extent, attributed to the lagged research on the structure of nematode chitinases. The availability of structure information could facilitate both structure-based virtual screening for inhibitor development and elucidation of inhibitory mechanism for inhibitor optimization [24][25][26][27] . Recently, we resolved the crystal structure of CeCht1 (PDB ID: 6LDU), a chitinase from the model nematode C. elegans 28 .…”

Structural dissection reveals a general mechanistic principle for group II chitinase (ChtII) inhibition

“…In our previous works, we observed that compounds bearing a large conjugated plane were likely to be potent inhibitors of GH18 chitinase (27,30). In this study, exploiting our previously reported two constructs of OfChtII (OfChtII-C1, residues 1606 -1992; OfChtII-C2, residues 2056 -2438) (8), we screened the compound library of our lab which contains a mass of compounds with a large conjugated plane and obtained four potent inhibitors.…”