State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, China.
Laboratory for Structural Bioinformatics, Center for Biosystems Dynamics Research, RIKEN, Yokohama, Japan.
J Enzyme Inhib Med Chem. 2021 Dec;36(1):1198-1204. doi: 10.1080/14756366.2021.1931862.
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 Cht1, a representative chitinase indispensable to the eggshell chitin degradation of the model nematode , we have discovered a series of novel inhibitors bearing a ()-3,4-diphenyl-4,5-dihydropyrrolo[3,4-]pyrazol-6(2)-one scaffold by hierarchical virtual screening. The crystal structures of Cht1 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 exhibited the most potent activity with a value of 0.18 μM. This work provides the structural basis for the development of novel nematode chitinase inhibitors.
线虫几丁质酶在各种生理过程中发挥着重要作用，包括卵孵化、幼虫蜕皮和繁殖。线虫几丁质酶的小分子抑制剂在防治线虫害虫方面具有潜在的应用价值。基于模式线虫卵壳几丁质降解所必需的代表性几丁质酶 Cht1 的晶体结构，我们通过分层虚拟筛选发现了一系列具有新型（）-3,4-二苯基-4,5-二氢吡咯并[3,4-]吡唑-6(2)-酮骨架的新型抑制剂。Cht1 与其中两种抑制剂复合物的晶体结构清楚地阐明了它们与酶活性位点的相互作用。基于抑制机制，鉴定出了几种抑制活性得到改善的类似物，其中化合物 表现出最强的活性， 值为 0.18 μM。这项工作为开发新型线虫几丁质酶抑制剂提供了结构基础。
