Kokel David, Bryan Jennifer, Laggner Christian, White Rick, Cheung Chung Yan J, Mateus Rita, Healey David, Kim Sonia, Werdich Andreas A, Haggarty Stephen J, Macrae Calum A, Shoichet Brian, Peterson Randall T
[1] Cardiovascular Research Center and Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA. [2] Broad Institute, Cambridge, Massachusetts, USA.
Nat Chem Biol. 2010 Mar;6(3):231-237. doi: 10.1038/nchembio.307. Epub 2010 Jan 17.
Neuroactive small molecules are indispensable tools for treating mental illnesses and dissecting nervous system function. However, it has been difficult to discover novel neuroactive drugs. Here, we describe a high-throughput, behavior-based approach to neuroactive small molecule discovery in the zebrafish. We used automated screening assays to evaluate thousands of chemical compounds and found that diverse classes of neuroactive molecules caused distinct patterns of behavior. These 'behavioral barcodes' can be used to rapidly identify new psychotropic chemicals and to predict their molecular targets. For example, we identified new acetylcholinesterase and monoamine oxidase inhibitors using phenotypic comparisons and computational techniques. By combining high-throughput screening technologies with behavioral phenotyping in vivo, behavior-based chemical screens can accelerate the pace of neuroactive drug discovery and provide small-molecule tools for understanding vertebrate behavior.
神经活性小分子是治疗精神疾病和剖析神经系统功能不可或缺的工具。然而，发现新型神经活性药物一直很困难。在此，我们描述了一种基于行为的高通量方法来在斑马鱼中发现神经活性小分子。我们使用自动化筛选试验评估了数千种化合物，发现不同类别的神经活性分子会引起不同的行为模式。这些“行为条形码”可用于快速识别新的精神活性化学物质并预测其分子靶点。例如，我们通过表型比较和计算技术鉴定了新的乙酰胆碱酯酶和单胺氧化酶抑制剂。通过将高通量筛选技术与体内行为表型分析相结合，基于行为的化学筛选可以加快神经活性药物的发现速度，并为理解脊椎动物行为提供小分子工具。
