Kokel D, Bryan J, Laggner C, White R, Cheung CY, Mateus R, Healey D, Kim S, Werdich AA, Haggarty SJ, Macrae CA, Shoichet B, Peterson RT. Rapid behavior-based identification of neuroactive small molecules in the zebrafish. Nat Chem Biol. 2010 Mar;6(3):231-237. PubMed.
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Pfizer
This is an interesting paper. The authors show that they are able to look for specific neuroactive signatures with high throughput using zebrafish embryos, and they can cluster compounds according to their functionality. They even do a modifier screen to look for revertants of a chemically induced deficit. With this screening approach, one can imagine screening large libraries for neuroactive substances and in parallel identify the molecular target.
Similar behavioral profiling approaches have been used in mice and rats, however, with lower throughput, of course, but a higher complicity and sensitivity of the tests. I personally like phenotypic screens. They are complex and difficult, but they can give the investigator completely new entry points or targets for drug discovery. With all the new -omics approaches identifying these targets, this is less difficult than it used to be.
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This paper reports an interesting systematic technique for monitoring the functional effects of certain neuroactive compounds. It monitors a series of phenotypic patterns and identifies those resulting from convergent signaling through different targets or pathways. This technique can identify novel chemotypes with similar target activities and potentially orthogonal biological responses to correct induced deficits, either genetic or pharmacological. Similar strategies have been used in the past, but this adds greater “molecular profiling” stringency in the analysis.
I can certainly see some companies adding this technique to their armamentarium of model systems that they might use to discover novel compounds exhibiting the neuroactive properties they are most interested in. The technique could also be useful to validate known targets from other indications, for safety issues (subtle neurotoxicity), and to triage compounds prior to further in-vivo testing in rodent or primate models.
That said, I also see certain limitations to its utility. For example, the concentration range of 10-100 micromolar for efficacy in this model is a significant rightward shift relative to on-target potency. This could mean that lower potency compounds—very often starting points for medicinal chemistry from high-throughput screens—are missed. I would like to see more data on the dynamic range of the assay (i.e., how quantitative is it?), and its performance against a truly random compound set (i.e., ones that have not already been optimized or pseudo-optimized against a target).
In summary, this is an innovative approach that could certainly attract interest and further validation as a novel technique for selecting neuroactive compounds. For a useful review on small molecule screening in zebrafish, see Murphey and Zon, 2006.
References:
Murphey RD, Zon LI. Small molecule screening in the zebrafish. Methods. 2006 Jul;39(3):255-61. PubMed.
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