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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.


Many drugs are structural analogs of each other. Hierarchical cluster tree of 42 drugs labeled as “antipsychotic” in the Drugbank database. Five major families are indicated with ovals. Each family stems from a single prototype molecule.
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Figure 1: Many drugs are structural analogs of each other. Hierarchical cluster tree of 42 drugs labeled as “antipsychotic” in the Drugbank database. Five major families are indicated with ovals. Each family stems from a single prototype molecule.

Mentions: Although the FDA lists thousands of antipsychotics, antidepressants and anxiolytics, most of these compounds fall into just a few structural classes. Consider the antipsychotics. Searching the FDALabel database for “antipsychotic” returns 1,325 hits, but most are mixtures and formulations of identical compounds (U.S. Food and Drug Administration, 2014). The same search in Drugbank returns 42 hits and most are close structural analogs of each other (Kokel and Peterson, 2008). Chemoinformatic algorithms cluster these compounds into a small number of structurally related families (Cao et al., 2008; Backman et al., 2011; Figure 1). Like antipsychotics, the antidepressants and anxiolytics show a similar pattern: There are many individual drugs, but most are structural analogs of a handful of prototypes. These data suggest that many drugs seem to discover themselves, due to the exploitation of prototype molecules (Sneader, 1996).


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

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

Many drugs are structural analogs of each other. Hierarchical cluster tree of 42 drugs labeled as “antipsychotic” in the Drugbank database. Five major families are indicated with ovals. Each family stems from a single prototype molecule.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Many drugs are structural analogs of each other. Hierarchical cluster tree of 42 drugs labeled as “antipsychotic” in the Drugbank database. Five major families are indicated with ovals. Each family stems from a single prototype molecule.
Mentions: Although the FDA lists thousands of antipsychotics, antidepressants and anxiolytics, most of these compounds fall into just a few structural classes. Consider the antipsychotics. Searching the FDALabel database for “antipsychotic” returns 1,325 hits, but most are mixtures and formulations of identical compounds (U.S. Food and Drug Administration, 2014). The same search in Drugbank returns 42 hits and most are close structural analogs of each other (Kokel and Peterson, 2008). Chemoinformatic algorithms cluster these compounds into a small number of structurally related families (Cao et al., 2008; Backman et al., 2011; Figure 1). Like antipsychotics, the antidepressants and anxiolytics show a similar pattern: There are many individual drugs, but most are structural analogs of a handful of prototypes. These data suggest that many drugs seem to discover themselves, due to the exploitation of prototype molecules (Sneader, 1996).

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.