Limits...
Discovering novel neuroactive drugs through high-throughput behavior-based chemical screening in the zebrafish.

Bruni G, Lakhani P, Kokel D - Front Pharmacol (2014)

Bottom Line: These compounds are powerful tools for understanding CNS signaling pathways.However, given the molecular genetic similarities between humans and zebrafish, it is likely that some of these compounds will have translational utility.We predict that the greatest new successes in CNS drug discovery will leverage many model systems, including in vitro assays, cells, rodents, and zebrafish.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School Charlestown, MA, USA.

ABSTRACT
Most neuroactive drugs were discovered through unexpected behavioral observations. Systematic behavioral screening is inefficient in most model organisms. But, automated technologies are enabling a new phase of discovery-based research in central nervous system (CNS) pharmacology. Researchers are using large-scale behavior-based chemical screens in zebrafish to discover compounds with new structures, targets, and functions. These compounds are powerful tools for understanding CNS signaling pathways. Substantial differences between human and zebrafish biology will make it difficult to translate these discoveries to clinical medicine. However, given the molecular genetic similarities between humans and zebrafish, it is likely that some of these compounds will have translational utility. We predict that the greatest new successes in CNS drug discovery will leverage many model systems, including in vitro assays, cells, rodents, and zebrafish.

No MeSH data available.


Behavioral phenotyping is a key bottleneck in drug discovery. Although there is an abundance of small molecules from nature, medicinal chemistry, and target-based screening only a very small number are ever tested in behavioral assays, limiting the drug discovery process.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4109429&req=5

Figure 2: Behavioral phenotyping is a key bottleneck in drug discovery. Although there is an abundance of small molecules from nature, medicinal chemistry, and target-based screening only a very small number are ever tested in behavioral assays, limiting the drug discovery process.

Mentions: Behavioral phenotyping is an essential part of drug discovery, but it is also the bottleneck (Figure 2). Prototype discovery often starts with the observation of an unexpected behavioral phenotype. Once a prototype has been identified, medicinal chemists generate structural analogs that themselves often have unexpected phenotypes. Researchers use these compounds to test therapeutic hypotheses and search for mechanistic understanding. When molecular targets are identified, researchers search for new ligands that trigger a new round of behavioral phenotyping. In target-based approaches, behavioral phenotyping is deferred until later in the process. Ultimately, the final step of determining efficacy in humans is also a matter of behavioral phenotyping. The process is incredibly effective and has generated most drugs that we use today. Medicinal chemistry can efficiently generate thousands of structural analogs; technologies for in vitro screening are ultra high-throughput. But, decades-old approaches to behavioral phenotyping throttle the drug discovery engine.


Discovering novel neuroactive drugs through high-throughput behavior-based chemical screening in the zebrafish.

Bruni G, Lakhani P, Kokel D - Front Pharmacol (2014)

Behavioral phenotyping is a key bottleneck in drug discovery. Although there is an abundance of small molecules from nature, medicinal chemistry, and target-based screening only a very small number are ever tested in behavioral assays, limiting the drug discovery process.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4109429&req=5

Figure 2: Behavioral phenotyping is a key bottleneck in drug discovery. Although there is an abundance of small molecules from nature, medicinal chemistry, and target-based screening only a very small number are ever tested in behavioral assays, limiting the drug discovery process.
Mentions: Behavioral phenotyping is an essential part of drug discovery, but it is also the bottleneck (Figure 2). Prototype discovery often starts with the observation of an unexpected behavioral phenotype. Once a prototype has been identified, medicinal chemists generate structural analogs that themselves often have unexpected phenotypes. Researchers use these compounds to test therapeutic hypotheses and search for mechanistic understanding. When molecular targets are identified, researchers search for new ligands that trigger a new round of behavioral phenotyping. In target-based approaches, behavioral phenotyping is deferred until later in the process. Ultimately, the final step of determining efficacy in humans is also a matter of behavioral phenotyping. The process is incredibly effective and has generated most drugs that we use today. Medicinal chemistry can efficiently generate thousands of structural analogs; technologies for in vitro screening are ultra high-throughput. But, decades-old approaches to behavioral phenotyping throttle the drug discovery engine.

Bottom Line: These compounds are powerful tools for understanding CNS signaling pathways.However, given the molecular genetic similarities between humans and zebrafish, it is likely that some of these compounds will have translational utility.We predict that the greatest new successes in CNS drug discovery will leverage many model systems, including in vitro assays, cells, rodents, and zebrafish.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School Charlestown, MA, USA.

ABSTRACT
Most neuroactive drugs were discovered through unexpected behavioral observations. Systematic behavioral screening is inefficient in most model organisms. But, automated technologies are enabling a new phase of discovery-based research in central nervous system (CNS) pharmacology. Researchers are using large-scale behavior-based chemical screens in zebrafish to discover compounds with new structures, targets, and functions. These compounds are powerful tools for understanding CNS signaling pathways. Substantial differences between human and zebrafish biology will make it difficult to translate these discoveries to clinical medicine. However, given the molecular genetic similarities between humans and zebrafish, it is likely that some of these compounds will have translational utility. We predict that the greatest new successes in CNS drug discovery will leverage many model systems, including in vitro assays, cells, rodents, and zebrafish.

No MeSH data available.