that followed the human genome project produced a flood of 50,000–75,000 sequences
as potential targets for future drug design. Despite the size of this flood, its flow has not
filled the drug discovery pipeline with winning candidates.
Determining gene structure and function through genomics definitely does illuminate
the path for deciphering human biochemistry and for linking specific genes to specific
diseases. Although genomics did deliver phenomenal masses of raw information, the
genomics technologies have so far failed to deliver the more than 10,000 anticipated
druggable targets predicted by the early hyperbole of the genomics era. Such success
will require post-genomics technologies. Taking genomics one step further for the pur-
pose of drug discovery will require linking specific proteins to those specific genes.
Clearly, there exists a vast gap between genomics and drug discovery. Bridging this gap
will ultimately be a daunting task that lies within the domain of proteomics.
3.2.7.2 Proteomics and Lead Compound Discovery
Proteomics is a protein-based science that seeks to provide new, fundamental informa-
tion about proteins on a genome-wide scale; to date, proteomics is still more of a con-
cept that a neatly defined smooth-running biotechnology. More concretely, proteomics
is the molecular biology discipline that seeks to elucidate the structure and function
profiles of all proteins encoded within a specific genome; this collection of proteins is
termed the proteome. The proteomes of multicellular organisms present an immense
challenge in that more than 75% of the predicted proteins have no apparent cellular
function. Furthermore, although the human proteome has more than 100,000 proteins,
only a fraction of these proteins are expressed in any individual cell type. If specific dis-
eases are to be linked to specific proteins, it is imperative that ways be developed to
deduce which individual protein is expressed in which individual cell.
Since protein and mRNA concentrations tend to be correlated,DNA microarray tech-
nology is a powerful technique with which to monitor the relative abundance of a spe-
cific mRNA in an individual cell and to correlate this with a specific protein.
(Regrettably, since mRNA and protein levels do not perfectly correlate, a direct mea-
surement of protein abundance would be preferable.) In addition to these microarray
technologies, many other technologies will be required if proteomics is to deliver the
drugs promised by genomics. For example, drug design requires much more than
merely knowing the primary amino acid sequence of a protein; it requires a precise
knowledge of the protein’s three-dimensional structure, down to the level of the
ångström. To date, science has no technology that enables one to use the information
coded in a protein’s primary amino acid sequence to deduce the overall tertiary struc-
ture of the protein. This is the multiple minima problem (also called the protein folding
problem) referred to in chapter 1. The need to solve this problem has given rise to the
subdiscipline of structural proteomics, a technology that is based upon the principle
that structure underlies function and that endeavors to provide three-dimensional struc-
tural information for all proteins.
Another evolving subdiscipline is interaction proteomics. Protein–protein interac-
tions are a key element of almost all cellular processes. These interactions underlie
the events of cell-cycle regulation, cellular architecture, intracellular signal transduction,
nucleic acid metabolism, lipid metabolism, and carbohydrate metabolism. A rigorous
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