Today’s paper is a continuation of our discussion on screening compounds for drug discovery: Kokel et al, 2010 Rapid behavior-based identification of neuroactive small molecules in the zebrafish, Nature Chemical Biology [PMC]. Having just returned from the IASP meeting in Montreal I am really pressed for time today so this is going to be brief; however, don’t let my brevity stop you from delving into the details of the paper — its a really fascinating study with major implications for drug discovery.
The problem is a simple one: when screening compounds we typically work on the assumption that the target for the disease is known. This is required because a typical library screen is based on receptor or enzyme activity and not a relevant behavioral phenotype. While this is fine for disorders with well understood targets, this is often not the case for neurobiological disorders where we don’t necessarily know the target beforehand. Hence, a behavior-based screening mechanism that is done in a high throughput fashion/screen (HTS) would be optimal for identifying novel neuroactive compounds. The problem is that behavioral experiments and model organisms are generally not conducive to this sort of thing:
Unlike target-based approaches, phenotype-based screens can identify compounds that produce a desired phenotype without a priori assumptions about their targets. Phenotype-based screens in cultured cells and whole organisms have identified powerful new compounds with novel activities on unexpected targets in vivo. However, it has been difficult to combine chemical-screening paradigms with behavioral phenotyping, perhaps because many well studied behaviors are too variable or occur in animals that are too large for screening in multi-well format.
So how have the authors provided a solution to this problem?