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screening and synthetic chemical library generation is markedly reshaping peptide, peptidomimetic, and
nonpeptide drug discovery research. In this chapter a few examples of peptidomimetic and nonpeptide
drug discovery are detailed to highlight the scope of such work relative to a few specific targets (e.g.,
receptors, proteases, and signal transduction proteins) in which structure-based drug design has
contributed in significant ways.
A. Peptides: Molecular Diversity and φ-Ψ-χ Space
Peptides exhibit extraordinary molecular diversity by virtue of their varying primary structures (Figure
1). For many peptide hormones, neurotransmitters, and releasing factors the substructure of amino acids
that contribute to molecular recognition (binding) and biological activity (signal transduction) at their
target receptors have been determined [2]. Such work has led to the generation of pharmacophore
models of either agonist or antagonist analogs and, in some cases, the design of peptidomimetics. Yet,
for most peptide growth factors, cytokines, and large-sized (>50 amino acids) peptide hormones, the
identification of the amino acid substructure which accounts for molecular recognition and signal
transduction has been a difficult task, and proposals for pharmacophore models remain significant
challenges. In this regard the term “pharmacophore” is defined as the collection of relevant groups
(substructure) of a ligand which are arranged in three-dimensional space in a manner complementary to
the target protein and are responsible for the biological property of the ligand as a result of binding of
the ligand to its target protein [8b].
The three-dimensional structural properties of peptides (Figure 2) are defined in terms of torsion angles
(Ψ, φ, ω, χ) between the backbone amine nitrogen (Nα), backbone carbonyl carbon (C'), backbone
methine carbon (Cα), and side chain hydrocarbon functionalization (eg., Cβ, Cγ, Cδ, Cε of Lys) derived
from the amino acid sequence. A Ramachandran plot (Ψ versus φ) may define the preferred
combinations of torsion angles for ordered secondary structures (conformations), such as α helix, β turn,
γ turn, or β sheet. With respect to the amide bond torsion angle (ω) the trans geometry is more
energetically favored for most typical dipeptide substructures, however, when the C-terminal partner is
Pro or other N-alkylated (including cyclic) amino acids the cis geometry is possible and may further
stabilize β-turn or γ-turn conformations. Molecular flexibility is directly related to covalent and/or
noncovalent bonding interactions within a particular peptide. Even modest chemical modifications by
Nα-methyl, Cα-methyl or Cβ-methyl can have significant consequences on the resultant conformation
[6; also, see Phe analogs in Figure 2].
The Nα-Cα-C' scaffold may be further transformed by introduction of olefin substitution (e.g., Cα-
Cβ rarrow.gif C=C or dehydroamino acid [19]) or insertion (e.g., Cα-C' rarrow.gif Cα-C=C-C' or
vinylogous amino acid [20]). Also the Cβ carbon may be substituted to advance the design of so-called
“chimeric” amino acids
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