Genomics Based Drug Discovery (1 of 4)

21世纪的到来被认为是生物医学研究的转折点。完整的 人类基因组的序列和密集的图谱，加上先进的基因组学技术，拥有 承诺极大地加速对人类疾病的理解，这反过来有望 加快发现新疗法的步伐。同样，合成有机材料的最新进展 化学具有极大地改进化学筛选和化合物优化的潜力。 原则上，这些技术和概念上的进步有可能改变药物发现。在……里面 然而，在实践中，他们还没有这样做。虽然新兴的基因组和化学技术正在 它们单独可用，尚未创造性地整合到药物发现过程中。一个关键原因 一直缺乏协调一致的跨学科努力来融合遗传学和化学学科 进入一个新的概念框架。 我们在这里提出了一个雄心勃勃的计划，创建一种新的药物发现方法，包括四个组成部分。 A部分(U54领导层)，包括IRC指导委员会。 组件B(发现管道)。这一部分旨在开发一个药物发现流水线， 关于表型筛选的范式。这包括开发i)系统的高通量 基于基因表达和成像的细胞状态表型分析的筛选；ii)扩展 DOS化合物文库，便于高通量筛选、靶标识别和药物 化学优化；以及iii)以基因组学为基础的预测毒理学方法。 组件C(目标ID)。该组件旨在开发系统的方法来识别 基于i)亲和捕获和蛋白质组学分析技术的小分子蛋白质靶标；ii) 使用RNA抑制(RNAi)的新方法；以及iii)识别 独特的细胞信号。 构成部分D(推动医疗项目)。为了推动其开发并测试其效用，新的 范式必须应用于特定的生物医学问题。这一构成部分将承担六项任务 示范项目。

The opening of the 21st century has been heralded as a turning point in biomedical research. The complete sequence and a dense map of the human genome, coupled with advanced genomics technologies holds the promise of dramatically accelerating the understanding of human disease, which in turn is expected to accelerate the pace of discovery of new therapeutics. Similarly, recent advances in synthetic organic chemistry have the potential to greatly improve chemical screening and compound optimization. In principle, these technical and conceptual advances have the potential to transform drug discovery. In practice, however, they have not yet done so. While emerging genomic and chemical technologies are available in isolation, they have not been creatively integrated into the drug discovery process. A key reason has been the lack of a concerted, interdisciplinary effort to merge the disciplines of genetics and chemistry into a new conceptual framework. We propose here an ambitious plan to create a new approach to drug discovery involving four components. Component A (U54 Leadership) which includes the IRC Steering Committee. Component B (Discovery Pipeline). This component aims to develop a drug discovery pipeline based on the paradigm of phenotypic screening. This includes developing i) systematic high-throughput screening of phenotypic assays for cellular states based on gene-expression and imaging; ii) expanded libraries of DOS compounds to facilitate high-throughput screening, target identification and medicinal chemistry optimization; and iii)genomics-based approaches to predictive toxicology. Component C (Target ID).This component aims to develop systematic approaches to identifying the protein target of a small molecule based on i) techniques for affinity capture and proteomic analysis; ii) novel approaches using RNA inhibition (RNAi); and iii) novel computational approaches to recognize distinctive cellular signatures. Component D (Driving Medical Projects). To drive its development and test its utility, the new paradigm must be applied to specific biomedical problems. This component will undertake six demonstration projects.