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opportunity for iterative structure-based drug design in this field or research (see below [86]). Relative
to Src SH2 domain antagonist lead discovery, peptide library studies [87] have shown the ~pTyr-Glu-
Glu-Ile~ as a preferred consensus sequence. Peptide scaffold-based approaches to replace the internal
dipeptide, Glu-Glu, by both flexible and rigid linkers have been explored [88] but were unsuccessful in
yielding potent analogs. As shown in Figure 16, prototype peptidomimetics 66 [77] and 67 [78] illustrate
a successful approach in which stereoinversion at the second residue (P+2 relative to the pTyr) to the Dconfiguration
and side chain substitution to hydrophobic functionalities (e.g., cyclohexyl and naphthyl)
which provides accessibility to the known hydrophobic binding pocket for the P+3 Ile side chain.
Indeed, such compounds showed binding affinities essentially identical to that of the N- and Cterminally
extended phosphopeptides containing the pTyr-Glu-Glu-Ile sequence. Substitution of the
pTyr residue of 66 by the difluoromethyl-phosphonate modified analog F 2Pmp provides a more
metabolically stable derivative 74 (Figure 16) and a prototype lead to advance the design of cellularly
active second-generation compounds. More recently, structure-based drug design studies of compound
65 have led to the discovery of potent and Src SH2-selective peptidomimetic lead compounds [89], and
this is further detailed below as related x-ray crystallographic structures of Src SH2-phosphopeptide
complexes.
III. Nonpeptide Ligand Lead Discovery and Structure-Based Drug Design
As previously illustrated in Figure 7, the convergent pathways to design drugs which act as mimics
(agonists), antagonists, or inhibitors of native peptide (protein) ligands at their target receptors,
proteases, signal-transduction proteins, and so forth, include “foreign” nonpeptides. The origin of such
nonpeptides may be either biological (e.g., natural product) or chemical (synthetic compound collection
or libraries) that have been subject to biochemical screening to identify leads for further molecular
design and structure-activity studies. Over recent years the success of screening-derived nonpeptide lead
discovery and iterative transformation to drug candidates has been quite impressive, and many aspects
of this area of research have been reviewed [12, 15]. Nevertheless, it is intriguing to explore the
potential relationship between peptide ligands (including peptidomimetic derivatives) and such
screening-derived nonpeptide ligands as related to pharmacophore modeling and structure-based drugdesign
studies.
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