Development of chemotype-phenotype database in zebrafish
With the dawn of molecular biology, target-based screening, which involves choosing a biological target based on a rational therapeutic hypothesis and subsequently screening for agents that modulate this particular target, has been the mainstay of drug discovery efforts. While target-based screens have been highly successful, there is a reviewed interest in phenotypic screens as a complementary approach. A phenotypic screen uses phenotype, an observable biological change, to identify chemotypes that engage functional targets in a meaningful and unbiased way. Zebrafish are a particularly useful biological model for large-scale phenotypic screens, due to their aquatic media, low cost, biologically conserved mechanisms, and rapid embryonic development. In a screen of 5000 compounds, from the diversity library at Vanderbilt, we annotated compounds that induced “nonspecific” toxicity or “specific” physiological/developmental defects. We hypothesized that toxic compounds will have more reactive chemical motifs resulting in more molecular targets, causing an inability of the embryo to account for the number of disruptions leading to organismal death. This will be in contrast to the compounds inducing a specific defect that we hypothesize will be less reactive and more specific. Finally, using a publically available genome-phenome database (ZFIN), we are developing chemotype-phenotype database to aid in target discovery.