Model Organisms in Drug Discovery

DROSOPHILA AS A MODEL ORGANISM FOR BIOMEDICAL SCIENCE 93
It has been recognized that fly genetics can be used for the identification of
target molecules and target pathways of selected compounds, the so-called
‘mechanism-of-action (MOA)’ studies (Matthews and Kopczynski, 2001). The
rationales are as follows. First of all, because of the general conservation
between fly and human genomes, a compound’s human target is likely to have
a fly homolog. Second, a compound-induced specific phenotype is due to
changed activity of its target molecule, thus it should be similar to the mutant
phenotype of the target gene. Third, genetic screens can be performed to find
mutants that suppress or enhance compound-induced phenotypes; some of
them should have mutations in the target molecule that affect the compound–
target interaction, or in other genes in the same pathway. Fourth, by finding
the mutant genes and subsequent analysis, the target genes and pathways can
be discovered.
The most important step in a MOA study of a compound is to find
compound-induced phenotypes that are specific, reliable and easily detectable.
Commonly used phenotypes include viability, fertility, behavior and
morphology. Phenotypes based on cellular markers may give better specificity
than gross phenotypes. Analysis of whole-genome expression profiles induced
by the compound can provide compound-specific ‘fingerprints’ and transcriptional
markers (Hughes et al., 2000). A dose–response curve should be
established. The best phenotype–dose pair for screening should be the one that
gives the largest phenotypic difference at the lowest compound dosage and
with minimal variation. If available, a structural derivative series of a
compound with different levels of bioactivity should be used to verify the
specificity of a phenotype.
One major theoretical concern of a fly MOA study is the potential high
background noise. For example, the phenotypic effect of a compound is
affected not only by its interaction with the target(s) but also strongly by its
absorption, distribution, metabolism and excretion (ADME). Thus, mutations
that suppress or enhance compound-induced phenotypes may be located
in genes affecting ADME rather than in the target molecule or target pathway.
Currently, there is no strong evidence to suggest that the knowledge of the fly
ADME mechanism can be extrapolated to the human ADME mechanism.
Thus, for the time being, mutations affecting a drug’s fly ADME are best
considered as noises in MOA studies. Because the molecular machinery
involved in ADME is not specific to any particular drug, methods can be
developed to separate mutations that affect ADME and other non-specific
mutations from the mutations that specifically affect drug target(s) and target
pathways. For example, several specificity tests can be established by using a
few highly specific compounds with well-known targets and associated
phenotypes. Mutations that can affect phenotypes induced by several of
these compounds are unlikely to be in the target molecules or target pathways
of the drug under study.