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cally-designed” peptidomimetics (or, as also defined, “peptoids” [106]). Nevertheless, screening-based
nonpeptide drug discovery has advanced a treasure of structure-function information to provide insight
into both structure-based design and molecular recognition [12,15,107]. In a few (limited) cases, there
exists a likely possibility of similar pharmacophoric features or substructural elements between
nonpeptides and their peptide-ligand counterparts (Figure 18).
Historically, drug discovery research on opioid GPCR receptor targets (e.g., μ, δ, κ) has provided insight
to explore the pharmacophores of both agonist and antagonists derived from endogenous peptides (e.g.,
endorphin, endorphin, and dynorphin) versus nonpeptides (e.g., the μ-receptor selective agonist
morphine and its N-allyl-substituted antagonist derivative naloxone). Relative to the N-terminal Tyr
moiety (side chain and α-amino functionalities) of the endogenous opioid peptides [108], the N-methyltyramine
substructure of morphine represents a likely common pharmacophore for agonist ligand
binding to the μ-receptor (Figure 18). In the case of angiotensin II receptor antagonist drug discovery, it
has been proposed [109] that a common pharmacophore may exist relative to the C-terminal His-Pro-
Phe-OH sequence of angiotensin II and nonpeptide 91 (Figure 18). In fact, these studies provided design
insight leading to the discovery of the drug candidate 77 (Lorsartan). A third example in which
correlation between peptide and nonpeptide pharmacophore models becomes apparent is that of
neuropeptide-Y (NPY) versus the benextramine-based derivative 92 [110] or arpromidine-based
derivative 93 [111] as illustrated in Figure 18. In both cases, the C-terminal Arg-Gln-Arg-Tyr-NH 2
sequence of NPY was modeled relative to the nonpeptide structures such that the guanido functionalities
were superimposed upon the corresponding basic (i.e., guanido or imidazole) substructural elements of
either 92 or 93.
In some cases, the availability of x-ray crystallographic information of both the peptide and nonpeptide
ligands may provide insight into the pharmacophore modeling studies. An example of this exists for
oxytocin antagonist structure-based drug design studies [112]. As shown in Figure 19, pharmacophore
models of both a cyclic hexapeptide oxytocin antagonists and conformationally-constrained,
tolylpiperazine camphorsulfonamide nonpeptide antagonist (89) suggest the likelihood of common
substructural elements that were key for molecular recognition at the oxytocin receptor, and led to the
design of a highly potent derivative 94. Nevertheless, such comparative pharmacophore “mapping”
studies are very simplistic since the 3D structures of the target receptors are not known. Furthermore,
site-directed mutagenesis studies
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