F Hoffmann-La Roche Ltd, pRED, Pharma Research & Early Development, Discovery Chemistry, CH-4070 Basel, Switzerland.
Drug Discov Today. 2012 Apr;17(7-8):325-35. doi: 10.1016/j.drudis.2012.01.001. Epub 2012 Jan 16.
The term 'pharmacological promiscuity' describes the activity of a single compound against multiple targets. When undesired, promiscuity is a major safety concern that needs to be detected as early as possible in the drug discovery process. The analysis of large datasets reveals that the majority of promiscuous compounds are characterized by recognizable molecular properties and structural motifs, the most important one being a basic center with a pK(a)(B)>6. These compounds interact with a small set of targets such as aminergic GPCRs; some of these targets attract surprisingly high hit rates. In this review, we discuss current trends in the assessment of pharmacological promiscuity and propose strategies to enable early detection and mitigation.
“药理学混杂性”一词描述了一种单一化合物对多种靶标的作用。当不期望出现这种情况时，混杂性是药物发现过程中需要尽早发现的主要安全问题。对大型数据集的分析表明，大多数混杂化合物具有可识别的分子特性和结构基序，最重要的是具有 pK(a)(B)>6 的碱性中心。这些化合物与一小部分靶标相互作用，如胺能 GPCR；其中一些靶标吸引了惊人的高命中率。在这篇综述中，我们讨论了评估药理学混杂性的当前趋势，并提出了一些策略来实现早期检测和缓解。
