Model Organisms in Drug Discovery

DROSOPHILA AS A MODEL ORGANISM FOR BIOMEDICAL SCIENCE 95
displacement or effect on target molecular function such as enzymatic activity.
In a cell-based assay, compound–target interaction is assayed indirectly based
on engineered readout that selectively represents the target activity. The
purified target-based assay is generally favored because it offers higher
throughput, greater exposure to chemical diversity, direct and detailed
knowledge of the kinetic or chemical MOA and a simple structure–activity
relationship (SAR) against the purified target. Cell-based assays are often used
as secondary or tertiary assays to examine the effect of compounds on the
target in a more relevant cellular environment and to select compounds with
better cellular penetration, activity and stability. In addition, cell-based
screens can discriminate between agonist, allosteric modulator and antagonist
activity that binding assays cannot, as well as provide information on the
acute cytotoxicity of compounds. The two-step serial method applies to many
intracellular targets such as enzymes.
In general, a cell-based assay is not favored for primary screens because the
cell membrane limits the screen range of pharmacophores, and hit compounds
may be found due to effects on other unknown molecules in the cells that give
the same readout, which makes subsequent SAR study difficult. However,
when a purified target-based assay is not feasible, a cell-based assay is used
instead, such as for voltage-gated ion channels, orphan receptors, other
targets expressed in the cell membrane, targets requiring assembly of a
complex that is difficult to reconstitute in vitro and for assaying changes in the
subcellular localization of a target. There is a general requirement for an assay
in a high-throughput screen to have an adequate dynamic range to separate
strongly active and weakly active compounds from the background noise
(Zhang et al., 1999). Optimization for cell-based assays can sometimes be very
challenging. Because of these limitations, non-mammalian-cell-based assays
sometimes provide unique opportunities.
In the absence of identified targets, cellular assays based on functional
readout can still be used for compound screens. In fact, the cell-based assay is
one of the oldest methods to generate lead compounds, and many drugs in the
market today were identified by this approach many decades ago (Moore and
Rees, 2001).
Potential benefits of compound screens in Drosophila
With some understanding of the current compound screen methodology, we
can now ask what value Drosophila cell/organism-based screens might offer
and when it is appropriate to use this approach. Drosophila, as well as
Drosophila cell lines, are made up of sophisticated machinery with a highly
interconnected network of dynamic molecular processes that are regulated by
internal and external signals. These evolutionary conserved machinery and