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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 Arp2/3复合体是由7种蛋白质组成的集合，通过促进肌动蛋白细丝分支的核化来调节肌动蛋白的动力学。由Arp2/3复合体功能形成的分支肌动蛋白网络在许多细胞过程中发挥核心作用，包括细胞运动、足体形成和病原体入侵宿主细胞。我们之前报道了两类小分子抑制剂的晶体结构，它们在体内和体内都能抑制Arp2/3复合体。这些化合物在低微摩尔范围内抑制IC50值的络合物。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络合物的结合能的影响。我们的最终目标是从原始化合物中获得具有低纳摩尔亲和力的抑制剂。这些抑制剂对于细胞生物学家研究Arp2/3复合体在体内的功能将是非常有价值的，并可能有助于抑制肿瘤细胞在转移过程中的迁移。

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.