Pengtao Yuan, Xi Jiang, Xintong Ni, Xusheng Shao, Xuhong Qian, Qing Yang
{"title":"发现构象受限的四环化合物作为有效的几丁质酶OfChi-h抑制剂,具有新的结合模式。","authors":"Pengtao Yuan, Xi Jiang, Xintong Ni, Xusheng Shao, Xuhong Qian, Qing Yang","doi":"10.1080/14756366.2025.2528056","DOIUrl":null,"url":null,"abstract":"<p><p>Chitinase h (Chi-h) has been identified as a promising pesticide target due to its exclusive distribution in lepidopteran insects and its essential role in the moulting processes. In this study, we leverage <i>Of</i>Chi-h from destructive agricultural pest <i>Ostrinia furnacalis</i> (Asian corn borer) as a model target to identify novel chitinase inhibitors. A conformational restriction approach was employed to design a series of novel <i>Of</i>Chi-h inhibitors. Among these, compound <b>6a</b> showed the highest inhibitory activity against <i>Of</i>Chi-h, with a <i>K<sub>i</sub></i> value of 58 nM. Molecular docking analysis suggested that <b>6a</b> tightly bound to three subsites (-3 to -1) of <i>Of</i>Chi-h. The binding mode is further confirmed by the co-crystallization data of <b>6a</b> with the <i>Sm</i>ChiA, a bacterial homologue of <i>Of</i>Chi-h, at a resolution of 1.8 Å. This research presents a novel approach for the development of highly potent insect chitinase inhibitors, offering potential tools for effective pest control.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2528056"},"PeriodicalIF":5.4000,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12239106/pdf/","citationCount":"0","resultStr":"{\"title\":\"Discovery of conformation constrained tetracyclic compounds as potent chitinase <i>Of</i>Chi-h inhibitors with a novel binding mode.\",\"authors\":\"Pengtao Yuan, Xi Jiang, Xintong Ni, Xusheng Shao, Xuhong Qian, Qing Yang\",\"doi\":\"10.1080/14756366.2025.2528056\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Chitinase h (Chi-h) has been identified as a promising pesticide target due to its exclusive distribution in lepidopteran insects and its essential role in the moulting processes. In this study, we leverage <i>Of</i>Chi-h from destructive agricultural pest <i>Ostrinia furnacalis</i> (Asian corn borer) as a model target to identify novel chitinase inhibitors. A conformational restriction approach was employed to design a series of novel <i>Of</i>Chi-h inhibitors. Among these, compound <b>6a</b> showed the highest inhibitory activity against <i>Of</i>Chi-h, with a <i>K<sub>i</sub></i> value of 58 nM. Molecular docking analysis suggested that <b>6a</b> tightly bound to three subsites (-3 to -1) of <i>Of</i>Chi-h. The binding mode is further confirmed by the co-crystallization data of <b>6a</b> with the <i>Sm</i>ChiA, a bacterial homologue of <i>Of</i>Chi-h, at a resolution of 1.8 Å. This research presents a novel approach for the development of highly potent insect chitinase inhibitors, offering potential tools for effective pest control.</p>\",\"PeriodicalId\":15769,\"journal\":{\"name\":\"Journal of Enzyme Inhibition and Medicinal Chemistry\",\"volume\":\"40 1\",\"pages\":\"2528056\"},\"PeriodicalIF\":5.4000,\"publicationDate\":\"2025-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12239106/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Enzyme Inhibition and Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/14756366.2025.2528056\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/7/7 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Enzyme Inhibition and Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/14756366.2025.2528056","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/7/7 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Discovery of conformation constrained tetracyclic compounds as potent chitinase OfChi-h inhibitors with a novel binding mode.
Chitinase h (Chi-h) has been identified as a promising pesticide target due to its exclusive distribution in lepidopteran insects and its essential role in the moulting processes. In this study, we leverage OfChi-h from destructive agricultural pest Ostrinia furnacalis (Asian corn borer) as a model target to identify novel chitinase inhibitors. A conformational restriction approach was employed to design a series of novel OfChi-h inhibitors. Among these, compound 6a showed the highest inhibitory activity against OfChi-h, with a Ki value of 58 nM. Molecular docking analysis suggested that 6a tightly bound to three subsites (-3 to -1) of OfChi-h. The binding mode is further confirmed by the co-crystallization data of 6a with the SmChiA, a bacterial homologue of OfChi-h, at a resolution of 1.8 Å. This research presents a novel approach for the development of highly potent insect chitinase inhibitors, offering potential tools for effective pest control.
期刊介绍:
Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents.
Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research.
The journal’s focus includes current developments in:
Enzymology;
Cell biology;
Chemical biology;
Microbiology;
Physiology;
Pharmacology leading to drug design;
Molecular recognition processes;
Distribution and metabolism of biologically active compounds.