Yao-Yao Jiang, Shuai-Ting Yan, Shan-Zhuo Zhang, Meng Wang, Wei-Ming Diao, Jun Li, Xiao-Min Fang, Hang Yin
{"title":"通过人工智能驱动的新一代筛选发现靶向 TLR4-TLR4* 同源二聚体的吡唑并[1,5-a]嘧啶衍生物","authors":"Yao-Yao Jiang, Shuai-Ting Yan, Shan-Zhuo Zhang, Meng Wang, Wei-Ming Diao, Jun Li, Xiao-Min Fang, Hang Yin","doi":"10.1016/j.ejmech.2024.116945","DOIUrl":null,"url":null,"abstract":"TLR4 signaling is instrumental in orchestrating multiple aspects of innate immunity. Developing small molecule inhibitors targeting the TLR4 pathway holds potential therapeutic promise for TLR4-related disorders. Herein, an artificial intelligence (AI)-powered next-generation screening approach, employing <em>HelixVS</em> and <em>HelixDock</em>, was utilized to focus on the TLR4−TLR4* (a second copy of TLR4) homodimerization surface, leading to the identification of a potent pyrazolo[1,5-<em>a</em>]pyrimidine derivative, designated as compound <strong>1</strong>. An extensive structure−activity relationship (SAR) exploration culminated in the discovery of the lead compound <strong>TH023</strong>, which effectively blocked the LPS-stimulated NF-κB activation and nitric oxide overproduction in HEK-Blue hTLR4 and RAW264.7 cells, with IC<sub>50</sub> values of 0.354 and 1.61 μM, respectively. Molecular dynamic (MD) simulations indicated that <strong>TH023</strong> stabilized TLR4−MD-2 and disrupted its association with TLR4*. Moreover, <strong>TH023</strong> alleviated the lung injury and decreased pro-inflammatory cytokine levels in LPS-induced septic mice. These findings not only illuminated the strategic advantage of <em>HelixDock</em> in advancing the frontiers of AI-driven drug discovery, but also provided valuable structural insights for the rational design of TLR4−TLR4* protein−protein interaction (PPI) inhibitors based on the pyrazolo[1,5-<em>a</em>]pyrimidine scaffold. Overall, this study validated a new strategy for TLR4 signaling regulation by targeting its dimerization, thereby underscoring the therapeutic promise of <strong>TH023</strong> in treating TLR4-mediated inflammatory diseases.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.0000,"publicationDate":"2024-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Discovery of Pyrazolo[1,5-a]pyrimidine Derivatives Targeting TLR4−TLR4* Homodimerization via AI-Powered Next-Generation Screening\",\"authors\":\"Yao-Yao Jiang, Shuai-Ting Yan, Shan-Zhuo Zhang, Meng Wang, Wei-Ming Diao, Jun Li, Xiao-Min Fang, Hang Yin\",\"doi\":\"10.1016/j.ejmech.2024.116945\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"TLR4 signaling is instrumental in orchestrating multiple aspects of innate immunity. Developing small molecule inhibitors targeting the TLR4 pathway holds potential therapeutic promise for TLR4-related disorders. Herein, an artificial intelligence (AI)-powered next-generation screening approach, employing <em>HelixVS</em> and <em>HelixDock</em>, was utilized to focus on the TLR4−TLR4* (a second copy of TLR4) homodimerization surface, leading to the identification of a potent pyrazolo[1,5-<em>a</em>]pyrimidine derivative, designated as compound <strong>1</strong>. An extensive structure−activity relationship (SAR) exploration culminated in the discovery of the lead compound <strong>TH023</strong>, which effectively blocked the LPS-stimulated NF-κB activation and nitric oxide overproduction in HEK-Blue hTLR4 and RAW264.7 cells, with IC<sub>50</sub> values of 0.354 and 1.61 μM, respectively. Molecular dynamic (MD) simulations indicated that <strong>TH023</strong> stabilized TLR4−MD-2 and disrupted its association with TLR4*. Moreover, <strong>TH023</strong> alleviated the lung injury and decreased pro-inflammatory cytokine levels in LPS-induced septic mice. These findings not only illuminated the strategic advantage of <em>HelixDock</em> in advancing the frontiers of AI-driven drug discovery, but also provided valuable structural insights for the rational design of TLR4−TLR4* protein−protein interaction (PPI) inhibitors based on the pyrazolo[1,5-<em>a</em>]pyrimidine scaffold. Overall, this study validated a new strategy for TLR4 signaling regulation by targeting its dimerization, thereby underscoring the therapeutic promise of <strong>TH023</strong> in treating TLR4-mediated inflammatory diseases.\",\"PeriodicalId\":314,\"journal\":{\"name\":\"European Journal of Medicinal Chemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.0000,\"publicationDate\":\"2024-10-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.ejmech.2024.116945\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ejmech.2024.116945","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Discovery of Pyrazolo[1,5-a]pyrimidine Derivatives Targeting TLR4−TLR4* Homodimerization via AI-Powered Next-Generation Screening
TLR4 signaling is instrumental in orchestrating multiple aspects of innate immunity. Developing small molecule inhibitors targeting the TLR4 pathway holds potential therapeutic promise for TLR4-related disorders. Herein, an artificial intelligence (AI)-powered next-generation screening approach, employing HelixVS and HelixDock, was utilized to focus on the TLR4−TLR4* (a second copy of TLR4) homodimerization surface, leading to the identification of a potent pyrazolo[1,5-a]pyrimidine derivative, designated as compound 1. An extensive structure−activity relationship (SAR) exploration culminated in the discovery of the lead compound TH023, which effectively blocked the LPS-stimulated NF-κB activation and nitric oxide overproduction in HEK-Blue hTLR4 and RAW264.7 cells, with IC50 values of 0.354 and 1.61 μM, respectively. Molecular dynamic (MD) simulations indicated that TH023 stabilized TLR4−MD-2 and disrupted its association with TLR4*. Moreover, TH023 alleviated the lung injury and decreased pro-inflammatory cytokine levels in LPS-induced septic mice. These findings not only illuminated the strategic advantage of HelixDock in advancing the frontiers of AI-driven drug discovery, but also provided valuable structural insights for the rational design of TLR4−TLR4* protein−protein interaction (PPI) inhibitors based on the pyrazolo[1,5-a]pyrimidine scaffold. Overall, this study validated a new strategy for TLR4 signaling regulation by targeting its dimerization, thereby underscoring the therapeutic promise of TH023 in treating TLR4-mediated inflammatory diseases.
期刊介绍:
The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers.
A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.