A Chemical Biology Network for Personalized Medicine

描述（由申请人提供）：生命的实时化学发生在细胞环境中存在的蛋白质和小化学物质的界面处。人类蛋白质组及其相互作用的化学基因组在历史上第一次以3D蛋白质结构数据库和NIH Pubchem化学文库的形式积累了足够的信息。此外，“互补算法”，准确地评估任何化学品和任何蛋白质表面之间的能量互补性或拟合最近已经变得可用，因为具有以高通量方式部署这些工具的计算能力。最后，系统生物学方法已经发展到这样的程度，即一旦互补算法对所有化学物质和所有蛋白质进行交叉评分，就可以可视化和探索生命实时化学相互作用的完整网络。我们建议在这里建立一个化学生物学网络来统一这些数据，沿着一个直观的网络界面，便于非定量生物医学研究人员使用。一旦部署，网络和附带的接口代表了一个关键的基础设施，可以大大加快协作，多学科和跨学科的基础，转化和/或临床研究，特别是通过为个性化医疗和传统药物开发工作提供新的药物开发途径。个体化医疗寻求识别患者的遗传特征通常是来自微阵列数据的高度复杂的概率表达特征与最佳治疗反应相关。本质上，可以用这些配置文件之一来查询所提出的化学生物学网络，并且可以立即检索到生物学匹配的类药物化合物的列表。这种工具将对临床试验完成和药物批准的速度产生深远的影响，因为历史表明，与生物标志物匹配的药物的临床试验，如her 2-neu和赫赛汀，进行得更快，成功率更高，成本也更低。此外，所提出的化学生物学网络可以通过先导化合物进行查询，并且可以立即检索具有相似生物活性的化学多样性化合物。这也可能加速药物的批准，因为为特定疗法并行推进多样化的先导化合物组合比推进单一化学类别更有可能迅速成功。FDA的关键路径计划（http：//www.fda.gov/oc/initiatives/criticalpath/initiative.html）明确阐述了通过利用本提案所针对的重大机遇所解决的挑战，这是NIH和FDA共同面临的一项前瞻性挑战，目前几乎没有解决方案。这一具体机会得益于所有必要要素的准备就绪，因此，尽管潜在影响巨大，但在ARRA的两年时间框架内，里程碑是高度可实现的。一旦建成，该网络具有未来几年低开销维护的综合优势，以及在地方，商业和政府层面扩展的多种高度适用的资金机会。因此，一旦建成，基础设施具有高度的可持续性和可扩展性，可用于美国生物医学研究企业的持续实用性。) 公共卫生相关性：由于RCSB蛋白质数据库的3D结构接近60，000个条目（人类基因组估计包含约20，000个基因），NIH的Pubchem数据库接近2000万种化学化合物，因此，2009年我们很可能可以获得大多数生命的3D结构以及化学空间多样性的信息样本。因此，将这两个基本的生物科学数据库交叉连接成一个单一的化学生物学网络，将基因、蛋白质靶点和潜在的化学疗法直接联系起来，这是一个巨大的机会。使用高通量计算方法，我们将建立这种关系网络，作为个性化医疗和药物发现的变革工具。

DESCRIPTION (provided by applicant): The real-time chemistry of life occurs at the interfaces of proteins and small chemicals present in the cellular environment. For the first time in history, sufficient information on the human proteome and its interacting chemogenome has accumulated in the form of the 3D protein structural database and the NIH Pubchem chemical library. In addition, 'complementarity algorithms', which accurately assess the energetic complementarity, or fit, between any chemical and any protein surface have recently become available, as has the computing power to deploy these tools in a high-throughput manner. Finally, systems biology methods have evolved to the point that the complete network of interactions of the real-time chemistry of life may be visualized and explored once complementarity algorithms have cross-scored all the chemicals to all the proteins. We propose here to build a chemical biology network to unify these data, along with an intuitive web interface for easy use by non-quantitative biomedical investigators. The network and accompanying interface, once deployed, represents a critical infrastructure that could substantially accelerate collaborative, multi- and interdisciplinary basic, translational, and/or clinical research, specifically by enabling new avenues of drug development for personalized medicine and traditional drug development efforts. Personalized medicine seeks to identify the genetic profiles of patients-frequently highly complex probabilistic expression profiles from microarray data--that correlate with optimal therapy responses. Essentially, the proposed chemical biology network may be queried with one of these profiles and a list of biologically matched drug-like chemical compounds would instantly be retrieved. Such a tool would have a profound impact on the rapidity of clinical trial completion and drug approval, as history has shown that clinical trials of drugs matched to biomarkers, such as her2-neu and Herceptin, proceed more rapidly and succeed more often at a much reduced cost. In addition, the proposed chemical biology network may be queried by lead compound and chemically diverse compounds with similar biological activity may be retrieved instantly. This, too, may accelerate drug approval as advancing a diverse portfolio of leads in parallel for a specific therapy is more likely to succeed rapidly than advancing a single chemical class. The challenge addressed by taking on the grand opportunity targeted by this proposal is elegantly articulated by the FDA's Critical Path Initiative (http://www.fda.gov/oc/initiatives/criticalpath/initiative.html), a forward- looking challenge that faces both the NIH and the FDA jointly, for which there are currently few solutions on the horizon. This specific opportunity benefits from the readiness of all the required elements, so that, despite the enormous potential impact, the milestones are highly achievable within the ARRA timeframe of two years. Once built, this network has the combined advantage of low overhead maintenance for future years, and multiple highly applicable funding opportunities for expansion at the local, commercial and governmental level. The infrastructure, once built, is thus highly sustainable and extensible for continued utility in the U.S. biomedical research enterprise. ) PUBLIC HEALTH RELEVANCE: As the RCSB Protein Data Bank of 3D structures nears 60,000 entries (with the human genome estimated to contain approximately 20,000 genes) and the NIH's Pubchem database nears 20 million chemical compounds, the possibility exists that the majority of the 3D structures of life as well as an informative sample of the diversity of chemical space is readily available to us in 2009. The grand opportunity thus presents itself to cross-connect these two elemental bioscientific databases into a single chemical biology network of direct links between genes, protein targets, and potential chemical therapeutics. Using high-throughput computational methods, we will build this network of relationships as a transformative tool for personalized medicine and drug discovery.