Drug Discovery in a Multidimensional World: Systems, Patterns, and Networks
Drug Discovery in a Multidimensional World: Systems, Patterns, and Networks
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DOI：
10.1007/s12265-010-9214-6
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发表时间：
2010-10-01
影响因子：
3.4
通讯作者：
Ashley, Euan
中科院分区：
文献类型：
--
作者：
Dudley, Joel T.;Schadt, Eric;Ashley, Euan
尽管在揭示和理解心血管疾病的生理和分子基础方面取得了很大进展，但将这种理解转化为必要的治疗干预措施的努力仍然远远落后于最初的发现。尽管制药公司继续增加对研发的投资，但获得联邦批准的药物数量正在下降。这些趋势背后有许多因素，人们正在通过重振药物发现管道的努力，寻求大量的技术和科学创新。分子图谱技术的最新进展和用于分析这些数据的复杂计算方法的发展正在为药物发现提供新的、面向系统的方法。与以一药一靶思维为代表的传统药物发现方法不同，面向系统的药物发现方法利用分子数据的并行性和高维性来构建更全面的分子模型，旨在对更广泛的双分子系统进行建模。这些模型提供了一种探索复杂分子状态(例如疾病)的方法，其中包括多种分子数据类型(例如蛋白质组学和基因表达)的数千到数百万个分子实体可以作为紧密结合的生物分子系统的组成部分同时被评估。在这篇文章中，我们讨论了面向系统的药物发现的新兴方法，并将这些努力与传统的单维药物发现方法进行了比较。我们还重点介绍了这些面向系统的方法在药物发现的各个方面的几个应用，包括靶标发现、药物重新定位和药物毒性。当可用时，突出和讨论心血管药物发现的具体应用。
Despite great strides in revealing and understanding the physiological and molecular bases of cardiovascular disease, efforts to translate this understanding into needed therapeutic interventions continue to lag far behind the initial discoveries. Although pharmaceutical companies continue to increase investments into research and development, the number of drugs gaining federal approval is in decline. Many factors underlie these trends, and a vast number of technological and scientific innovations are being sought through efforts to reinvigorate drug discovery pipelines. Recent advances in molecular profiling technologies and development of sophisticated computational approaches for analyzing these data are providing new, systems-oriented approaches towards drug discovery. Unlike the traditional approach to drug discovery which is typified by a one-drug-one-target mindset, systems-oriented approaches to drug discovery leverage the parallelism and high-dimensionality of the molecular data to construct more comprehensive molecular models that aim to model broader bimolecular systems. These models offer a means to explore complex molecular states (e. g., disease) where thousands to millions of molecular entities comprising multiple molecular data types (e. g., proteomics and gene expression) can be evaluated simultaneously as components of a cohesive biomolecular system. In this paper, we discuss emerging approaches towards systems-oriented drug discovery and contrast these efforts with the traditional, unidimensional approach to drug discovery. We also highlight several applications of these system-oriented approaches across various aspects of drug discovery, including target discovery, drug repositioning and drug toxicity. When available, specific applications to cardiovascular drug discovery are highlighted and discussed.