IDENTIFYING MC1-1 INHIBITORS USING POCKET SHAPE OPTIMIZATION

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 癌症是一种植根于蛋白质-蛋白质相互作用失调的疾病;这些包括细胞增殖、分化和死亡的潜在机制。尽管通过高通量筛选（HTS）引起了强烈的兴趣和相当大的努力，但直接抑制蛋白质-蛋白质相互作用的小分子的例子很少。这表明大多数蛋白质相互作用表面不是药物靶点，或者目前的HTS文库不太适合这项任务。最近的一项调查确定了一些蛋白质结构的例子，这些蛋白质结构既与生物蛋白质伴侣复合，也与小分子抑制剂复合  包括重要的癌蛋白如Bcl-xL的列表。未结合的蛋白质结构与小分子复合物中的等效结构的比较表明，虽然结合与大的构象变化无关，但小分子结合的蛋白质表面上的凹口袋通常不存在于载脂蛋白结构中。 我的实验室目前专注于使用计算机模拟来预测蛋白质（小分子结合）的全息构象从载脂蛋白（未结合）构象，假设不知道小分子的身份。在这个COBRE CET应用程序中，我们建议使用映射Bcl-2家族每个成员的蛋白质表面上可能出现的口袋形状的集合。与药物化学实验室一起，我们将使用这个“口袋形状库”来制备互补小分子的靶向库。与高通量筛选实验室一起，我们将筛选该文库的已知蛋白质-蛋白质相互作用的体外抑制和体内活性。 由于我们的文库将来自靶蛋白的口袋形状，我们预计我们的方法将特别适合于鉴定具有新化学型的抑制剂（“支架跳跃”）。因此，我们预计我们的新方法将导致识别新的抑制性化合物，为这个家庭的充分验证的目标。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Cancer is a disease rooted in the disregulation of protein-protein interactions; these comprise the underlying mechanisms for cell proliferation, differentiation, and death. Despite intense interest and considerable effort via high-throughput screening (HTS), there are few examples of small-molecules that directly inhibit protein-protein interactions. This suggests either that most protein interaction surfaces are not druggable targets, or else that current HTS libraries are not well-suited for this task. A recent survey identified the few examples of protein structures that have been solved both in complex with a biological protein partner and also in complex with a small molecule inhibitor  a list that includes important oncoproteins such as Bcl-xL. Comparison of the unbound protein structure to the equivalent structure in complex with a small molecule shows that while binding is not associated with a large conformational change, the concave pocket on the protein surface in which the small molecule binds is typically absent in the apo structure. My lab is currently focused on using computer simulations to predict the holo conformation of a protein (small-molecule bound) from the apo (unbound) conformation, assuming no knowledge of the small molecule's identity. In this COBRE CCET application, we propose to use map the ensemble of possible pocket shapes that can occur on the protein surface for each member of the Bcl-2 family. Together with the Medicinal Chemistry Laboratory, we will use this "pocket shape library" to prepare a targeted library of complementary small-molecules. In conjunction with the High Throughput Screening Laboratory, we will then screen this library for in vitro inhibition of the known protein-protein interaction and for in vivo activity. Since our library will derive from pocket shapes of the target protein, we expect that our method will be particularly well poised to identify inhibitors with new chemotypes ("scaffold hopping"). We therefore anticipate our novel approach will lead to identification of new inhibitory compounds for this family of well-validated targets.