ANCHOR: A PDB-Wide Real Time Discovery Resource of Novel PPI (Ant)-agonists

描述（由申请人提供）：目前的药物发现合作主要集中在商业可用化合物的大型库的高通量筛选上。这种固定的模式为化学家和生物学家之间的协同作用提供了很少的机会。我们寻求从蛋白质-蛋白质相互作用（PPI）的结构信息中获益，以蛋白质数据库（PDB）为例，开始采用PDB-全系统生物学方法，结合生物物理学见解，多组分反应（MCR）化学，和先进的计算机科学来开发一个全新的开放的-访问技术，促进生物学家之间的真正合作，谁是专家对特定的蛋白质-蛋白质相互作用（PPI）和化学家谁拥有专业知识，设计，发现和开发小分子量化合物。我们的方法建立在锚侧链的作用之上：侧链深埋在PPI的受体蛋白中，并识别出定义明确的“可药物化”口袋。 我们使用化学模拟的一个锚作为切入点到MCR的合理设计-可访问的小分子量化合物。与传统的多步顺序合成相反，MCR化学将先进的起始材料组装成一种新产品，从而大大节省了成本和时间。作为一个概念的证明，我们已经开发并验证了一种基于网络的技术，这种技术可以将真实的合理的药物设计带到任何科学家的笔记本电脑上。通过用户友好的界面，研究人员可以利用他们的见解和专业知识来设计药效团，并在几秒钟内从20多个不同的反应中筛选数百万种有偏见的MCR-可访问的化合物。使用我们的方法，当靶向p53-MDM 2 PPI时，我们获得了大约50%的命中率。我们的具体目标是：（a）扩大我们的新型MCR--可访问的虚拟化合物库所涵盖的化学空间和目标;（B）提高我们的虚拟筛选技术的排名、优化和其他分析能力;（C）积极吸引全球研究小组参与体外和/或体内测定，目标是开发小分子量（抗）激动剂。基于虚拟筛选技术的结果，我们（或其他人）将能够快速合成预测的化合物。我们的最终目标是为生物医学研究人员提供直接访问虚拟筛选技术和数量有限的潜在活性新化合物，供他们在内部小规模筛选能力中使用。然后可以将活性命中物优化为化学探针，以研究基因、细胞和生化途径的功能。这种变革性的资源必将带来探索基因和信号通路在健康和疾病中的功能的新方法。

DESCRIPTION (provided by applicant): Current drug discovery collaborations are mainly centered on the high---throughput screening of large libraries of commercially available compounds. This fixed modality provides little opportunity for synergy between chemists and biologists. We seek to benefit from the increasing amount of structural information on protein---protein interactions (PPIs), exemplified by the Protein Data Bank (PDB), to embark in a PDB---wide systems biology approach that combines biophysical insights, multiple component reaction (MCR) chemistry, and advanced computer science to develop a radically new open---access technology that facilitates true collaboration between biologists who are experts on specific protein---protein interactions (PPIs) and chemists who have the expertise to design, discover and develop small molecular weight compounds. Our approach builds on the role of anchor side chains: side chains that are deeply buried in the acceptor protein of the PPI and identify well---defined "druggable" pockets. We use chemical mimicry of an anchor as an entry point into the rational design of MCR---accessible small molecular weight compounds. Contrary to traditional multistep sequential synthesis, MCR chemistry assembles advanced starting materials into a new product in a one---pot procedure resulting in a tremendous savings in cost and time. As a proof---of---concept, we have developed and validated a web---based technology that brings real---time rational drug design to the laptop of any scientist. Through a user---friendly interface, researchers can use their insights and expertise to design pharmacophores and screen millions of biased MCR---accessible compounds from over 20 distinct reactions in a matter of seconds. Using our approach we have obtained around a 50% hit rate when targeting the p53---MDM2 PPI. Our specific aims are to: (a) expand the chemical space and targets covered by our libraries of novel, MCR---accessible virtual compounds; (b) improve the ranking, optimization and other analytical capabilities of our virtual screening technology; and (c) actively engage worldwide research groups with in vitro and/or in vivo assays with the goal of developing small molecular weight (ant)agonists. Based on the results of the virtual screening technology, we (or others) will be able to rapidly synthesize the predicted compounds. Our ultimate goal is to offer biomedical researchers direct access to virtual screening technologies and a limited number of potentially active novel compounds for them to use in their in---house small---scale screening capabilities. Active hits can then be optimized as chemical probes to study the functions of genes, cells, and biochemical pathways. This transformative resource is bound to lead to new ways to explore the functions of genes and signaling pathways in health and disease.