...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Protein-protein interaction inhibition (2P2I) combining high throughput and virtual screening: Application to the HIV-1 Nef protein
【24h】

Protein-protein interaction inhibition (2P2I) combining high throughput and virtual screening: Application to the HIV-1 Nef protein

机译：结合高通量和虚拟筛选的蛋白质-蛋白质相互作用抑制（2P2I）：在HIV-1 Nef蛋白质中的应用

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Protein-protein recognition is the cornerstone of multiple cellular and pathological functions. Therefore, protein-protein interaction inhibition (2P2I) is endowed with great therapeutic potential despite the initial belief that 2P2I was refractory to small-molecule intervention. Improved knowledge of complex molecular binding surfaces has recently stimulated renewed interest for 2P2I, especially after identification of "hot spots" and first inhibitory compounds. However, the combination of target complexity and lack of starting compound has thwarted experimental results and created intellectual barriers. Here we combined virtual and experimental screening when no previously known inhibitors can be used as starting point in a structure-based research program that targets an SH3 binding surface of the HIV type I Nef protein. High-throughput docking and application of a pharmacophoric filter on one hand and search for analogy on the other hand identified drug-like compounds that were further confirmed to bind Nef in the micromolar range (isothermal titration calorimetry), to target the Nef SH3 binding surface (NMR experiments), and to efficiently compete for Nef-SH3 interactions (cell-based assay, GST pull-down). Initial identification of these compounds by virtual screening was validated by screening of the very same library of compounds in the cell-based assay, demonstrating that a significant enrichment factor was attained by the in silico screening. To our knowledge, our results identify the first set of drug-like compounds that functionally target the HIV-1 Nef SH3 binding surface and provide the basis for a powerful discovery process that should help to speed up 2P2I strategies and open avenues for new class of antiviral molecules.
机译：蛋白质-蛋白质识别是多种细胞和病理功能的基石。因此，尽管最初认为2P2I对小分子干预是难治的，但蛋白质-蛋白质相互作用抑制（2P2I）具有巨大的治疗潜力。最近，对复杂分子结合表面的了解不断增强，引起了人们对2P2I的重新关注，尤其是在确定“热点”和第一种抑制性化合物之后。然而，目标复杂性和缺乏起始化合物的结合阻碍了实验结果并造成了智力上的障碍。当没有以前已知的抑制剂可以用作针对HIV I型Nef蛋白的SH3结合表面的基于结构的研究程序的起点时，我们将虚拟和实验筛选结合起来。高通量对接和一方面应用药效团过滤器，另一方面寻找相似之处，鉴定出类药物化合物，这些化合物被进一步证实可在微摩尔范围内结合Nef（等温滴定量热法），以靶向Nef SH3结合表面（NMR实验），并有效竞争Nef-SH3相互作用（基于细胞的测定，GST下拉）。通过虚拟筛选对这些化合物进行的初步鉴定通过在基于细胞的测定法中筛选非常相同的化合物文库进行了验证，表明通过计算机筛选获得了显着的富集因子。据我们所知，我们的研究结果确定了第一套功能性靶向HIV-1 Nef SH3结合表面的类药物化合物，并为强大的发现过程提供了基础，该发现过程应有助于加快2P2I策略并为新型的P2I开辟道路抗病毒分子。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

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