ACADIA Pharmaceuticals Inc., 3911 Sorrento Valley Boulevard, San Diego, CA, 92121, USA,
Cytotechnology. 2002 Jan;38(1-3):3-10. doi: 10.1023/A:1021169023731.
Chemical genomics is a new research paradigm with importantapplications in drug discovery. It links genomic targets withsmall-molecule chemistries thereby allowing for efficient targetvalidation and lead compound identification. ACADIA'schemical-genomics platform consists of a large and diverse small-moleculelibrary (800,000), a reference drug library (2,000), druggablegenomic targets (>300) and a cell-based functional assaytechnology (R-SAT(TM); Receptor Selection and AmplificationTechnology) that allows for ultra-high throughput screening(>500,000 data points/week) as well as high throughputpharmacology and profiling over a wide range of targets. Twoexamples are presented that illustrate the success of ourchemical-genomics approach: (i) The validation of inverse agonismat serotonin 5-HT(2A) receptors as an antipsychotic mechanismand the subsequent discovery of potent and selectively acting 5-HT(2A) inverse agonists, currently in preclinical development,and (ii) the discovery of the first ectopically binding subtype-selective muscarinic m1 agonist.
化学生物学是一种新的研究范例，在药物发现中有重要的应用。它将基因组靶点与小分子化学物质联系起来，从而能够有效地进行靶标验证和先导化合物鉴定。ACADIA 的化学生物学平台由一个大型的、多样化的小分子库（80 万种）、一个参考药物库（2000 种）、可成药的基因组靶点（>300 个）和一种基于细胞的功能测定技术（R-SAT（TM）；受体选择和扩增技术）组成，该技术可实现超高通量筛选（>500000 个数据点/周）以及针对广泛靶点的高通量药理学和剖析。本文呈现了两个成功应用化学生物学方法的实例：（i）验证了 5-羟色胺 5-HT（2A）受体的反向激动作用作为一种抗精神病机制，随后发现了具有强大和选择性作用的 5-HT（2A）反向激动剂，目前正在临床前开发中，（ii）发现了第一个异位结合的亚型选择性毒蕈碱 m1 激动剂。
