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Nonmessenger Targets for Drug Action II

Endogenous macromolecules

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8.1 Endogenous Macromolecules: Relevant Biochemistry

If targeting messenger molecules such as neurotransmitters, hormones, or
immunomodulators fails to address the disease under study, the next approach is to target
either nonmessenger endogenous structures, such as the cell membrane or cell nucleus
(see chapter 7), or nonmessenger endogenous macromolecules such as proteins (enzymes)
or lipids (prostaglandins) (this chapter). These endogenous macromolecules are the cat-
alysts and molecular machinery that enable the cell to perform its normal metabolic
functions; accordingly, they afford numerous druggable targets.
At the molecular level, the human body is constructed from a diverse array of mole-
cules and macromolecules that can be broadly categorized into seven general groupings:

1. Water


2. Amino acids, peptides, proteins


3. Lipids


4. Carbohydrates


5. Nucleosides, nucleotides, nucleic acids


6. Heterocycles


7. Minerals and inorganic salts

These seven groups of compounds, and the diversity of compounds within each group,
are the molecular building blocks that enable structure and function. A brief overview
of the relevant biochemistry for each class is pertinent to an appreciation of their role
in medicinal chemistry and drug design.

8.1.1 Water

Water is the single most common molecule in the human body. Indeed, the human
body is 73–76% water. Although it is the most ubiquitous molecule, it is the molecule
that is most conspicuously ignored during drug design. Water is a powerful molecular