{"title":"反式查尔酮在体内鸡绒毛尿囊素膜模型中的抗血管生成潜力:一种具有预测血脑屏障通透性的VEGFR ATP拮抗剂。","authors":"Anna Senrung, Tanya Tripathi, Nikita Aggarwal, Divya Janjua, Arun Chhokar, Joni Yadav, Apoorva Chaudhary, Kulbhushan Thakur, Tejveer Singh, Alok Chandra Bharti","doi":"10.2174/0118715257250417231019102501","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma multiforme (GBM) is characterized by massive tumorinduced angiogenesis aiding tumorigenesis. Vascular endothelial growth factor A (VEGF-A) via VEGF receptor 2 (VEGFR-2) constitutes majorly to drive this process. Putting a halt to tumordriven angiogenesis is a major clinical challenge, and the blood-brain barrier (BBB) is the prime bottleneck in GBM treatment. Several phytochemicals show promising antiangiogenic activity across different models, but their ability to cross BBB remains unexplored.</p><p><strong>Methods: </strong>We screened over 99 phytochemicals having anti-angiogenic properties reported in the literature and evaluated them for their BBB permeability, molecular interaction with VEGFR-2 domains, ECD2-3 (extracellular domains 2-3) and TKD (tyrosine kinase domain) at VEGF-A and ATP binding site, cell membrane permeability, and hepatotoxicity using <i>in silico</i> tools. Furthermore, the anti-angiogenic activity of predicted lead Trans-Chalcone (TC) was evaluated in the chick chorioallantoic membrane.</p><p><strong>Results: </strong>Out of 99 phytochemicals, 35 showed an efficient ability to cross BBB with a probability score of > 0.8. Docking studies revealed 30 phytochemicals crossing benchmark binding affinity < -6.4 kcal/mol of TKD with the native ligand ATP alone. Out of 30 phytochemicals, 12 showed moderate to low hepatotoxicity, and 5 showed a violation of Lipinski's rule of five. Our <i>in silico</i> analysis predicted TC as a BBB permeable anti-angiogenic compound for use in GBM therapy. TC reduced vascularization in the CAM model, which was associated with the downregulation of VEGFR-2 transcript expression.</p><p><strong>Conclusion: </strong>The present study showed TC to possess anti-angiogenic potential <i>via</i> the inhibition of VEGFR-2. In addition, the study predicted TC to cross BBB as well as a safe alternative for GBM therapy, which needs further investigation.</p>","PeriodicalId":93924,"journal":{"name":"Cardiovascular & hematological agents in medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Anti-angiogenic Potential of Trans-chalcone in an <i>In Vivo</i> Chick Chorioallantoic Membrane Model: An ATP Antagonist to VEGFR with Predicted Blood-brain Barrier Permeability.\",\"authors\":\"Anna Senrung, Tanya Tripathi, Nikita Aggarwal, Divya Janjua, Arun Chhokar, Joni Yadav, Apoorva Chaudhary, Kulbhushan Thakur, Tejveer Singh, Alok Chandra Bharti\",\"doi\":\"10.2174/0118715257250417231019102501\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Glioblastoma multiforme (GBM) is characterized by massive tumorinduced angiogenesis aiding tumorigenesis. Vascular endothelial growth factor A (VEGF-A) via VEGF receptor 2 (VEGFR-2) constitutes majorly to drive this process. Putting a halt to tumordriven angiogenesis is a major clinical challenge, and the blood-brain barrier (BBB) is the prime bottleneck in GBM treatment. Several phytochemicals show promising antiangiogenic activity across different models, but their ability to cross BBB remains unexplored.</p><p><strong>Methods: </strong>We screened over 99 phytochemicals having anti-angiogenic properties reported in the literature and evaluated them for their BBB permeability, molecular interaction with VEGFR-2 domains, ECD2-3 (extracellular domains 2-3) and TKD (tyrosine kinase domain) at VEGF-A and ATP binding site, cell membrane permeability, and hepatotoxicity using <i>in silico</i> tools. Furthermore, the anti-angiogenic activity of predicted lead Trans-Chalcone (TC) was evaluated in the chick chorioallantoic membrane.</p><p><strong>Results: </strong>Out of 99 phytochemicals, 35 showed an efficient ability to cross BBB with a probability score of > 0.8. Docking studies revealed 30 phytochemicals crossing benchmark binding affinity < -6.4 kcal/mol of TKD with the native ligand ATP alone. Out of 30 phytochemicals, 12 showed moderate to low hepatotoxicity, and 5 showed a violation of Lipinski's rule of five. Our <i>in silico</i> analysis predicted TC as a BBB permeable anti-angiogenic compound for use in GBM therapy. TC reduced vascularization in the CAM model, which was associated with the downregulation of VEGFR-2 transcript expression.</p><p><strong>Conclusion: </strong>The present study showed TC to possess anti-angiogenic potential <i>via</i> the inhibition of VEGFR-2. In addition, the study predicted TC to cross BBB as well as a safe alternative for GBM therapy, which needs further investigation.</p>\",\"PeriodicalId\":93924,\"journal\":{\"name\":\"Cardiovascular & hematological agents in medicinal chemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cardiovascular & hematological agents in medicinal chemistry\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.2174/0118715257250417231019102501\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cardiovascular & hematological agents in medicinal chemistry","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.2174/0118715257250417231019102501","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Anti-angiogenic Potential of Trans-chalcone in an In Vivo Chick Chorioallantoic Membrane Model: An ATP Antagonist to VEGFR with Predicted Blood-brain Barrier Permeability.
Background: Glioblastoma multiforme (GBM) is characterized by massive tumorinduced angiogenesis aiding tumorigenesis. Vascular endothelial growth factor A (VEGF-A) via VEGF receptor 2 (VEGFR-2) constitutes majorly to drive this process. Putting a halt to tumordriven angiogenesis is a major clinical challenge, and the blood-brain barrier (BBB) is the prime bottleneck in GBM treatment. Several phytochemicals show promising antiangiogenic activity across different models, but their ability to cross BBB remains unexplored.
Methods: We screened over 99 phytochemicals having anti-angiogenic properties reported in the literature and evaluated them for their BBB permeability, molecular interaction with VEGFR-2 domains, ECD2-3 (extracellular domains 2-3) and TKD (tyrosine kinase domain) at VEGF-A and ATP binding site, cell membrane permeability, and hepatotoxicity using in silico tools. Furthermore, the anti-angiogenic activity of predicted lead Trans-Chalcone (TC) was evaluated in the chick chorioallantoic membrane.
Results: Out of 99 phytochemicals, 35 showed an efficient ability to cross BBB with a probability score of > 0.8. Docking studies revealed 30 phytochemicals crossing benchmark binding affinity < -6.4 kcal/mol of TKD with the native ligand ATP alone. Out of 30 phytochemicals, 12 showed moderate to low hepatotoxicity, and 5 showed a violation of Lipinski's rule of five. Our in silico analysis predicted TC as a BBB permeable anti-angiogenic compound for use in GBM therapy. TC reduced vascularization in the CAM model, which was associated with the downregulation of VEGFR-2 transcript expression.
Conclusion: The present study showed TC to possess anti-angiogenic potential via the inhibition of VEGFR-2. In addition, the study predicted TC to cross BBB as well as a safe alternative for GBM therapy, which needs further investigation.