Model Organisms in Drug Discovery

DROSOPHILA AS A MODEL ORGANISM FOR BIOMEDICAL SCIENCE 91
510 75 as cutoff identifies about 2200 orthologs. This class of fly genes has
high predictive power for the function of the corresponding human genes.
However, many of these genes encode proteins for basic cellular machinery,
such as basic transcription, splicing, translation and replication apparatus.
Many of them are less likely to be drug targets.
2. Low-confidence orthologs. This class of genes still has a one-to-one
relationship with their human counterparts but, because the level of
sequence homology is lower, the confidence level about information
transfer to human genes is lower.
3. High-confidence homologs. This class of genes has equivalent homology to
multiple human genes, and homology is throughout most of the encoded
protein sequences. It is important to note that two genes may not be
considered good homologs if the homology between the two protein
sequences is restricted only to a small region and the containing protein
domain is prevalent in the genomes, such as the protein kinase domain or
Ankyrin repeat. This one-to-many class of fly genes makes it difficult, if not
impossible, to predict which human homolog is more relevant. It requires
commitment of considerable resources for experimental determination in
mammalian systems. On the other hand, the single corresponding fly gene
may carry out all or some of the functions of one or more of the human
homologs, so functional analysis of the fly gene can reveal insights into the
function of the human genes while avoiding the masking effects of
functional redundancy in mammals.
4. Low-confidence homologs. This class of fly genes maintains the one-to-many
property but with lower sequence homology. The double-negatives make
this gene class less attractive.
5. Insect-specific genes. The insect-specific genes have received less attention
from the pharmaceutical industry than from agricultural industry.
However, these genes can provide drug targets for insect-borne diseases,
such as malaria or dengue fever, by aiming at the homologs in the insect
vectors.
Drugability of target proteins: valuable filter or moving target?
The value of fly genes in drug discovery is not solely determined by their
sequence homology to human genes. The biochemical/molecular functions of
the encoded proteins have a strong influence on their values in the near future.
Among the 500 targets of marketed drugs today, the majority belong to a
limited number of protein families (Drews, 2000). For example, 45% of
known targets are receptors, 28% are enzymes, 11% are hormones and