Biomedical Engineering Reference
In-Depth Information
As a rule of thumb, the better studied a protein is, the larger the scope of its poten-
tial cellular activities is reported in the literature, suggesting that some degree of
multifunctionality [1] might be a common attribute of all biological macromolecules.
For example, it is not uncommon for metabolic enzymes to form complexes with
other cellular components, affecting each other's spatial distribution and functions.
Each protein activity is mediated through binding to a different partner, either a
small-molecule metabolite or a cellular macromolecule, and is likely to rely on a
distinct binding area within the protein molecule. Unfortunately, variations observed
in the protein expression levels associated with diseases are not capable of singling
out which of the known (or yet-unknown) activities of the protein might be involved
in the pathophysiological manifestation. Thus, selective small-molecule compounds,
targeting a specific binding event, are necessary for zooming in on specific pro-
tein functions involved with a disease. These compounds, commonly referred to as
chemical probes , provide invaluable chemical biology tools.
Chemogenomics is a research discipline responsible for identification of these
selective molecules, with the overall goal of finding chemical probes for each potential
binding site of macromolecules [2]. Understandably, discrimination of binding sites
through selectivity of the site recognition is a prerequisite for the biological utility
of chemical probes. In a broad sense, chemogenomics represents “aligning” the
chemical universe with a universe of biological macromolecules, or more specifically,
their binding sites. This is clearly an unattainable task if one is to rely on a pairwise
compound-target matching approach. Recent advances in the synthetic chemistry and
biological screening disciplines will certainly make this task less daunting, even if
not readily attainable in the new future.
One of the major synthetic chemistry advances over the past decade is an emer-
gence and maturation of diversity-oriented synthesis (DOS) methodologies, described
in detail in other chapters. This approach enables the production of libraries of thou-
sands to tens of thousands of structurally diverse compounds. Theoretically, DOS
compound collections represent a renaissance of combinatorial library approaches
fashionable a decade and a half ago. In reality, DOS methodologies surpass the lim-
its inherent in combinatorial libraries of the past by augmenting the appendage and
functional group variability nascent in combinatorial libraries with unprecedented
scaffold and stereochemical diversity embedded in the design of DOS libraries and
enabled by the aforementioned advances in synthetic chemistry.
DOS compounds are carefully designed and created through a series of intricate
synthetic steps. Despite the complex chemistry leading to the generation of DOS col-
lections, the resulting compound structures are foreseeable and could be confirmed
easily, or if necessary, established through straightforward and conclusive tests pro-
viding an objective picture of a compound's degree of diversity. On the other hand,
the spectrum of biological activity of any given DOS compound is an unknown and
a priori unforeseeable property; it has to be established through extensive experi-
mental testing against a diverse panel of biological targets. The methodology elected
for testing compounds is normally defined by the size of compound collections,
which are on the order of thousands to tens of thousands of compounds in a typical
DOS collection. Testing sizable compound collections is usually performed in the
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