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首页> 外文会议>Conference on Methods and Applications of Fluorescence: Spectroscopy, Imaging, and Probes >Single-bead, Single-molecule,Single-cell Fluorescence Technologies for Drug Screening and Target Validation
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Single-bead, Single-molecule,Single-cell Fluorescence Technologies for Drug Screening and Target Validation

机译：用于药物筛选和目标验证的单珠，单分子，单细胞荧光技术

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According to many current reports, the pharmaceutical business will hit a wall over the next fewyears. The generic competition is expected to wipe out a double-digit billion-dollar amount fromtop companies' annual sales between 2007 and 2012 (Wall StreetJournal, online, December 6, 2007).The industry's science engine has stalled, new blockbusters are lacking, and patent expirationsare a big problem. Also, the U.S. Food and Drug Administration is pulling back on approvals,requesting larger safety studies. Among the different approaches taken throughout the industry toimprove productivity and to reduce the attrition rate of compounds in the drug discovery process,an extended application of quantitative biology and biophysical methods is ranked very high.Fluorescence spectroscopy and imaging represented the main detection technologies for assaysand screening methods in recent years. Today, label-free detection methods, such as isothermaltitration calorimetry, differential scanning calorimetry, tandem mass spectrometry (MS"), lightscattering, or interferometry, start to provide viable alternative readouts for physicochemicalcharacterization ofleads and hit list triaging. However, the multidimensional nature of fluorescencealong with its high sensitivity and single-molecule resolution remains an unparalleled source ofmolecular parameters to extract all different kinds of information on molecules and ligand-proteincomplexes in solution. Although fluorescence-based methods are currently applied throughout thedifferent stages of the industrial drug discovery process, they are usually applied in an unconnectedway. We have developed a fully integrated hit and lead discovery process combining bead-basedsynthesis and screening methods with confocal fluorescence microspectroscopy. The primary on-bead screening process provides fluorescent ligands that after a multistep characterization processultimately leads to fully mechanistically characterized cellularly validated binders and inhibitors oftarget protein interactions. The unlabeled small-molecular inhibitors represent chemical startingpoints in drug discovery and target validation.
机译：根据许多当前报告，制药业务将在下几年击中墙壁。通用竞争预计将消除2007年至2012年期间的两位数二亿美元的年销售额（Wall Streetjournal，在线，2007年12月6日）。业界的科学引擎已经停滞不前，缺乏新的大块牌缺失，而且专利期限是一个大问题。此外，美国食品和药物管理局正在重新批准，要求更大的安全研究。在整个行业采取的不同方法中，为了减少药物发现过程中化合物的磨损率，量化生物学和生物物理方法的扩展应用是非常高的。荧光光谱和成像代表了ASSAYSAND筛选的主要检测技术近年来的方法。如今，无标签检测方法，如等温altitritoration热量测定法，差分扫描量热法，串联质谱（MS“），光散射或干涉测量，开始为情人和命中列表三环的物理化学特征化提供可行的替代读数。但是，多维本质荧义肠病具有高灵敏度和单分子分辨率，仍然是分子分子参数的无与伦比的来源，以提取溶液中分子和配体 - 蛋白质复合物的所有不同类型的信息。虽然目前在工业药物发现过程的层次阶段目前应用于荧光的方法，但是它们通常在未连接的道路中应用。我们开发了一个完全集成的命中和引导发现过程，将珠子基合成和筛选方法与共聚焦荧光微旋光术相结合。主要的珠子筛选过程提供了多层炭的荧光配体。 Percerization Pricionultime导致完全机械验证的细胞验证的粘合剂和抑制剂的蛋白质相互作用。未标记的小分子抑制剂代表了药物发现和目标验证中的化学出发点。

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