IMPROVING SMALL MOLECULE INHIBITORS OF ARP2/3 COMPLEX WITH FREE ENERGY PERTURBA

利用自由能扰动改进 ARP2/3 复合物的小分子抑制剂

• 批准号: 8171897
• 负责人: Bradley J Nolen
• 金额: $ 0.11万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171897
• 关键词: Actins; Affinity; Binding; Cell physiology; Cells; Chemicals; Complex; Computer Retrieval of Information on Scientific Projects Database; Filament; Free Energy; Funding; Goals; Grant; Inhibitory Concentration 50; Institution; Microfilaments; Neoplasm Metastasis; Play; Proteins; Reporting; Research; Research Personnel; Resources; Role; Source; Structure; United States National Institutes of Health; cell motility; improved; in vivo; inhibitor/antagonist; pathogen; small molecule

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Arp2/3 complex is an assembly of seven proteins which regulates actin dynamics by promoting the nuclation of actin filament branches from pre-existing filaments. Branched actin networks created by Arp2/3 complex function play a central role in many cellular processes, including cell motility, podosome formation and invasion of host cells by pathogens. We previously reported the crystal structures of two classes of small molecule inhibitors which inhibit Arp2/3 complex in vito and in vivo. These compounds inhibit the complex with IC50 values in the low micromolar range. Here we propose to use free energy perturbation calculations to computationally explore the effect of small chemical alterations on the compounds on their energy of binding to the complex. Our ultimate goal is to derive inhibitors with low nanomolar affinity from the original compounds. Such inhibitors will be invaluable for cell biologists studying Arp2/3 complex function in vivo and may be useful in inhibiting migration of tumor cells during metastasis.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 Arp2/3 复合体是七种蛋白质的组装体，它通过促进肌动蛋白丝分支从预先存在的丝中成核来调节肌动蛋白动力学。由 Arp2/3 复合体功能创建的分支肌动蛋白网络在许多细胞过程中发挥着核心作用，包括细胞运动、足体形成和病原体对宿主细胞的入侵。我们之前报道了两类在体外和体内抑制 Arp2/3 复合物的小分子抑制剂的晶体结构。这些化合物抑制复合物，IC50 值在低微摩尔范围内。在这里，我们建议使用自由能微扰计算来计算探索化合物上的微小化学变化对其与复合物结合的能量的影响。我们的最终目标是从原始化合物中衍生出具有低纳摩尔亲和力的抑制剂。此类抑制剂对于细胞生物学家研究体内 Arp2/3 复合物功能非常有价值，并且可能有助于抑制肿瘤细胞在转移过程中的迁移。