diffusion, an appropriate developing agent is sprayed on the agar surface and areas
in which bioactivity has occurred will show up as distinct zones)- Affinity selection assays (compound library is applied to a protein target receptor; all
compounds that do not bind are removed; compounds that do bind are then identified)
Of these, microplate assays are probably the most widely used. Screening combinator-
ial libraries in 96- or even 384-well microplates is time and cost efficient. Using
modern robotic techniques, it is possible to perform more than 100,000 bioassays per
week in a microplate system (permitting the above-described 200,000 compound
library to be screened in two weeks, rather than over a century).
In addition to selecting an appropriate assay, it is also necessary to have a pooling
strategy. It is more efficient to test many compounds per well on the microplate, rather
than one. If one could test 100 compounds per well, then the standard 96-well plate
would enable almost 10,000 compounds to be evaluated in one experiment. (Currently,
multiwell plates containing more than 96 wells are routinely being used.) To facilitate
effective pooling, the library of compounds is usually divided into a number of
nonoverlapping subsets.
The synthetic strategy employed during the combinatorial syntheses can be used to
assist in determining these pooling strategies. In random incorporation syntheses,a
single bead could contain millions of different molecular species. In mix and split syn-
theses(also called pool and divide synthesesorone bead–one compound syntheses)
only one compound is attached to any given solid-phase synthetic bead.
The evolution of methods for combinatorial syntheses and high throughput screening
will be necessary to address the explosion of druggable targets soon to be identified by
the genomics and proteomics revolutions. Genomics and proteomics represent the
future of lead compound identification.
3.2.7 Lead Compound Identification through Genomics and ProteomicsConservative estimates suggest that more than 4000 human diseases are influenced by
distinct and potentially targetable (or druggable) genetic factors. Current drug design
strategies are struggling with fewer than 500 druggable receptor proteins. Endeavoring
to identify lead compounds for an additional 3500 targets will overwhelm present-day
drug design technologies. Drug design has come a long way since the unfortunate
demise of King Charles II, but clearly it has a very long way to go. Genomics and pro-
teomics represent a possible pathway to enhanced future drug discovery.
3.2.7.1 Genomics and Lead Compound Discovery
Genomics is the study of genes and their functions. On June 26, 2000–the dawning of
the present century–a historic milestone in genomic science was attained when
researchers involved with the Human Genome Project jointly announced that they had
sequenced 97–99% of the human genome–the all-encompassing collection of human
genes. The human genome consists of 23 pairs of chromosomes with three billion base
pair codes for approximately 24,000–30,000 functional genes (original estimates of
100,000–120,000 genes seem to have been incorrectly high). The genomic gold rush
DESIGNING DRUG MOLECULES TO FIT RECEPTORS 125