• 主题
高级搜索  >
历史搜索 清空历史
首页> 美国卫生研究院文献>Drug Design Development and Therapy >Combining structure-based pharmacophore modeling virtual screening and in silico ADMET analysis to discover novel tetrahydro-quinoline based pyruvate kinase isozyme M2 activators with antitumor activity
【2h】

Combining structure-based pharmacophore modeling virtual screening and in silico ADMET analysis to discover novel tetrahydro-quinoline based pyruvate kinase isozyme M2 activators with antitumor activity

机译：结合基于结构的药效团建模虚拟筛选和计算机模拟ADMET分析发现具有抗肿瘤活性的新型基于四氢喹啉的丙酮酸激酶同工酶M2激活剂

代理获取
本网站仅为用户提供外文OA文献查询和代理获取服务，本网站没有原文。下单后我们将采用程序或人工为您竭诚获取高质量的原文，但由于OA文献来源多样且变更频繁，仍可能出现获取不到、文献不完整或与标题不符等情况，如果获取不到我们将提供退款服务。请知悉。
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Compared with normal differentiated cells, cancer cells upregulate the expression of pyruvate kinase isozyme M2 (PKM2) to support glycolytic intermediates for anabolic processes, including the synthesis of nucleic acids, amino acids, and lipids. In this study, a combination of the structure-based pharmacophore modeling and a hybrid protocol of virtual screening methods comprised of pharmacophore model-based virtual screening, docking-based virtual screening, and in silico ADMET (absorption, distribution, metabolism, excretion and toxicity) analysis were used to retrieve novel PKM2 activators from commercially available chemical databases. Tetrahydroquinoline derivatives were identified as potential scaffolds of PKM2 activators. Thus, the hybrid virtual screening approach was applied to screen the focused tetrahydroquinoline derivatives embedded in the ZINC database. Six hit compounds were selected from the final hits and experimental studies were then performed. Compound 8 displayed a potent inhibitory effect on human lung cancer cells. Following treatment with Compound 8, cell viability, apoptosis, and reactive oxygen species (ROS) production were examined in A549 cells. Finally, we evaluated the effects of Compound 8 on mice xenograft tumor models in vivo. These results may provide important information for further research on novel PKM2 activators as antitumor agents.
机译：与正常分化的细胞相比，癌细胞上调丙酮酸激酶同工酶M2（PKM2）的表达以支持糖酵解中间体的合成代谢过程，包括核酸，氨基酸和脂质的合成。在这项研究中，结合了基于结构的药效团建模和虚拟筛选方法的混合方案，包括基于药效团模型的虚拟筛选，基于对接的虚拟筛选和计算机模拟ADMET（吸收，分布，代谢，排泄和毒性） ）分析用于从市售化学数据库中检索新型PKM2激活剂。四氢喹啉衍生物被确定为PKM2激活剂的潜在支架。因此，混合虚拟筛选方法被应用于筛选嵌入在ZINC数据库中的聚焦四氢喹啉衍生物。从最终命中中选择了六个命中化合物，然后进行了实验研究。化合物8显示出对人肺癌细胞的有效抑制作用。用化合物8处理后，检查了A549细胞的细胞活力，凋亡和活性氧（ROS）产生。最后，我们评估了化合物8对体内小鼠异种移植肿瘤模型的影响。这些结果可能为进一步研究新型PKM2激活剂作为抗肿瘤药物提供重要信息。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
代理获取

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号