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。

Anna Senrung, Tanya Tripathi, Nikita Aggarwal, Divya Janjua, Arun Chhokar, Joni Yadav, Apoorva Chaudhary, Kulbhushan Thakur, Tejveer Singh, Alok Chandra Bharti
{"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}
引用次数: 0

摘要

背景:多形性胶质母细胞瘤(GBM)以大量肿瘤诱导的血管生成辅助肿瘤发生为特征。血管内皮生长因子A(VEGF-A)通过VEGF受体2(VEGFR-2)主要驱动这一过程。阻止肿瘤驱动的血管生成是一项重大的临床挑战,血脑屏障(BBB)是GBM治疗的主要瓶颈。几种植物化学物质在不同的模型中显示出有希望的抗血管生成活性,但它们穿越血脑屏障的能力仍有待探索。方法:我们筛选了文献中报道的99多种具有抗血管生成特性的植物化学物质,并使用计算机工具评估了它们的血脑屏障通透性、与VEGFR-2结构域、ECD2-3(细胞外结构域2-3)和TKD(酪氨酸激酶结构域)在VEGF-A和ATP结合位点的分子相互作用、细胞膜通透性和肝毒性。此外,在鸡胚绒毛尿囊膜中评估了预测的铅反式查尔康(TC)的抗血管生成活性。结果:在99种植物化学物质中,35种表现出有效的穿越血脑屏障的能力,概率得分>0.8。对接研究揭示了30种植物化学物质跨越基准结合亲和力结论:本研究表明TC通过抑制VEGFR-2具有抗血管生成的潜力。此外,该研究预测TC可以穿过血脑屏障,也是GBM治疗的安全替代方案,需要进一步研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
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.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
自引率
0.00%
发文量
0
期刊最新文献
Cardio-metabolic Disorders Affected by Genetic Polymorphisms Related to Premature Menopause. Factor Xa Inhibitors and Low Molecular Weight Heparins in Perioperative Surgical Thromboprophylaxis: A Network Meta-Analysis. Iron Deficiency and its Relationship with Chronic Heart Failure- A Review. Sodium Butyrate, a Gut Microbiota Derived Metabolite, in Type 2 Diabetes Mellitus and Cardiovascular Disease: A Review. The Effect of CD31 on Coronary Collateral Development.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1