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

ANCHOR：新型 PPI（Ant）激动剂的 PDB 范围实时发现资源

• 批准号: 8727052
• 负责人: Carlos J. Camacho
• 金额: $ 31.37万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8727052
• 关键词: Agonist; Alzheimer' s Disease; Amino Acids; Ants; Binding; Biochemical; Biochemical Pathway; Biochemistry; Biological; Biological Assay; Biology; Cells; Cellular biology; Chemicals; Chemistry; Collaborations; Collection; Computer Simulation; Computing Methodologies; Custom; Databases; Development; Discipline; Disease; Docking; Drug Design; Effectiveness; Ephrins; Funding; Generations; Goals; Health; Hot Spot; Housing; Human; Imagery; In Vitro; Intervention; Knowledge; Lead; Libraries; Ligands; MDM2 gene; Malignant Neoplasms; Medical; Methods; Modality; Molecular Bank; Molecular Conformation; Molecular Weight; Online Systems; Pharmaceutical Preparations; Pharmacologic Substance; Procedures; Process; Proteins; Rare Diseases; Reaction; Relative (related person); Research; Research Personnel; Resources; Role; Savings; Scientist; Shapes; Side; Signaling Pathway Gene; Staging; Systems Biology; Technology; Time; Tryptophan; United States National Institutes of Health; Validation; Virtual Library; analog; base; chemical synthesis; combinatorial; computer science; conformer; cost; design; drug discovery; gene function; high throughput screening; improved; in vivo; inhibitor/antagonist; insight; interest; laptop; mimicry; novel; pharmacophore; protein protein interaction; receptor; scaffold; screening; structural biology; tool; user-friendly; virtual

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.

描述(由申请人提供)：目前的药物发现合作主要集中在高通量筛选大型商业可用化合物文库。这种固定的模式为化学家和生物学家之间的协同提供了很少的机会。我们寻求从以蛋白质数据库(PDB)为代表的关于蛋白质-蛋白质相互作用(PPI)的越来越多的结构信息中受益，开始采用PDB范围的系统生物学方法，该方法结合了生物物理学的见解、多组分反应(MCR)化学和先进的计算机科学，以开发一种全新的开放访问技术，促进特定蛋白质-蛋白质相互作用(PPI)专家的生物学家和具有设计、发现和开发小分子化合物专业知识的化学家之间的真正合作。我们的方法建立在锚定侧链的作用上：这种侧链深深地埋在PPI的受体蛋白中，并识别出定义明确的“可用药”口袋。我们使用锚的化学模拟作为合理设计MCR的切入点-可访问的小分子化合物。与传统的多步顺序合成相反，MCR化学通过一锅法将先进的起始材料组装成新产品，从而极大地节省了成本和时间。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，它将实时合理的药物设计带到任何科学家的笔记本电脑上。通过一个用户友好的界面，研究人员可以利用他们的洞察力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出数百万有偏见的MCR-可访问化合物。使用我们的方法，当针对P53-MDM2 PPI时，我们已经获得了大约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靶标；(B)提高我们的虚拟筛选技术的排名、优化和其他分析能力；以及(C)积极与世界各地的研究小组进行体外和/或体内测试，以开发小分子量(ANT)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有限数量的潜在活性新化合物的机会，供他们在内部小规模筛选能力中使用。然后，活性HITS可以被优化为化学探针，以研究基因、细胞和生化途径的功能。这种变革性的资源必然会导致探索基因和信号通路在健康和疾病中的功能的新方法。