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.