Maximizing the identification of leads from compound mixtures
Maximizing the identification of leads from compound mixtures
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DOI：
10.2174/157018007780077408
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发表时间：
2007-04-01
影响因子：
1
通讯作者：
Burns, David J.
中科院分区：
文献类型：
--
作者：
Warrior, Usha;Gopalakrishnan, Sujatha M.;Burns, David J.
高通量筛选（HTS）已成为药物发现的关键部分，用于识别特定疾病靶点的潜在先导分子。筛选的成功是通过几个因素来衡量的，包括检测的通量和成本，但最终是通过药物发现管道向前发展的HTS命中的数量。通过从96孔到384孔到1536威尔斯孔到无孔平台的转换来实现测定的小型化，以及利用自动化设备是实现增加通量和降低筛选成本的方法。合并测试化合物也是一种有效的方法，虽然有争议，以提高筛选通量，同时降低试剂成本。在此，我们描述了在雅培实验室实施的具体措施，以提高10-混合物正交筛选的效率，以及为降低假阳性率和消除假阴性而制定的策略。从混合物与单一化合物筛选的比较研究的结果将讨论三种不同的筛选格式：GPCR功能测定，GPCR结合测定和酪氨酸激酶测定。
High throughput screening (HTS) has become a pivotal part of drug discovery for identifying potential lead molecules for specific disease targets. The success of screening is measured by several factors including the throughput and cost of the assays, but ultimately by the number of HTS hits that progress forward through the drug discovery pipeline. Miniaturization of assays by conversion from 96- to 384- to 1536- wells to well-less platforms, and the utilization of automated equipments are methodologies implemented to increase the throughput and reduce the cost of the screen. Pooling of test compounds is also an effective, though controversial method to enhance screening throughput while reducing reagent costs. Herein, we describe specific measures implemented at Abbott Laboratories to enhance the efficiency of 10-mixture orthogonal screening, and the strategy developed to reduce the rate of false positives and eliminate false negatives. Results from a comparison study of mixtures versus single compound screening will be discussed for three distinct screening formats: a GPCR functional assay, a GPCR binding assay and a tyrosine kinase assay.