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

文献类型： 外文期刊

第一作者： Chen, Wei

作者： Chen, Wei;Chen, Qi;Yang, Qing;Kumar, Ashutosh;Zhang, Kam Y. J.;Jiang, Xi;Yang, Qing;Yang, Qing

作者机构：

关键词： Nematode chitinase; inhibitor; inhibitory mechanism; structural optimisation

期刊名称：JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY （ 影响因子：5.051； 五年影响因子：4.598 ）

ISSN： 1475-6366

年卷期： 2021 年 36 卷 1 期

页码：

收录情况： SCI

摘要： Nematode chitinases play vital roles in various physiological processes, including egg hatching, larva moulting, and reproduction. Small-molecule inhibitors of nematode chitinases have potential applications for controlling nematode pests. On the basis of the crystal structure of CeCht1, a representative chitinase indispensable to the eggshell chitin degradation of the model nematode Caenorhabditis elegans, we have discovered a series of novel inhibitors bearing a (R)-3,4-diphenyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(2H)-one scaffold by hierarchical virtual screening. The crystal structures of CeCht1 complexed with two of these inhibitors clearly elucidated their interactions with the enzyme active site. Based on the inhibitory mechanism, several analogues with improved inhibitory activities were identified, among which the compound PP28 exhibited the most potent activity with a K (i) value of 0.18 mu M. This work provides the structural basis for the development of novel nematode chitinase inhibitors.

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