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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH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 中心，不一定是研究者的机构。 Arp 2/3复合物是由七种蛋白质组成的集合体，通过促进肌动蛋白丝分支从预先存在的丝成核来调节肌动蛋白动力学。由Arp 2/3复合体功能产生的分支肌动蛋白网络在许多细胞过程中起着核心作用，包括细胞运动、足体形成和病原体入侵宿主细胞。我们以前报道了两类在体和体内抑制Arp 2/3复合物的小分子抑制剂的晶体结构。这些化合物以低微摩尔范围内的IC 50值抑制复合物。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小化学变化对它们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获得具有低纳摩尔亲和力的抑制剂。这种抑制剂将是非常宝贵的细胞生物学家研究Arp 2/3复杂的功能在体内，并可能是有用的，在转移过程中抑制肿瘤细胞的迁移。

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.