Do Zebrafish Obey Lipinski Rules?

The use of zebrafish in whole organism phenotypic assays has become a valuable strategy throughout the drug discovery process. Zebrafish assays can be used not only to screen libraries of compounds at the earliest stages but also to evaluate advanced leads for their effects on specific biological pathways or for toxicity. However, when confronted with inactivity of a compound in a zebrafish assay, there are little data that can be used to judge if the compound is truly biologically inert or inactive due to a lack of permeability into the model organism. While medicinal chemistry principles suggest parameters that are predictive of human oral bioavailability, cellular permeability, and even bacterial permeability, there have been no such parameters developed for zebrafish absorption. To address this question, we compiled a set of 700 compounds reported in the literature to be active in zebrafish assays, evaluated their properties, and compared them to properties derived from a set of historical drugs and a set of recently approved oral drugs. While some properties overlap, the averages and 10th and 90th percentiles of molecular weight, octanol-water partition coefficient (logP), H-bond counts, and polar surface area for zebrafish-active compounds are statistically different from those of known drugs. This analysis should be useful to scientists interpreting structure-activity relationships based on data from zebrafish assays and help to inform the translation from fish to mammals.