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several PTP1B residues at the surface proximate to the well-defined pTyr binding pocket. Such 3D
structural information provides insight for the design of peptidomimetic inhibitors of PTP1B.
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In the case of the IRS-1 PTB domain, x-ray crystallographic studies of PTB complexed with a pTyrcontaining
peptide (134) complex have shown (Figure 32) that the phosphopeptide forms a type-I β-turn
within the Asn-Pro-Ala-pTyr sequence, and the peptide backbone is extensively hydrogen bonded to the
PTB domain from the P +1-P -7 residues of 134 [261]. The pTyr binding pocket provides both electrostatic
and multiple hydrogen bonding contacts to the phosphate ester moiety, and hydrophobic interactions
exist for the P -1-P -3 side chains of the peptide. As in the case of PTP1B, such 3D structural information
provides the opportunity for structure-based drug design to discover potent inhibitors which may be used
for further exploration in cellular studies.
V. Future Perspectives
The impact of structure-based drug design on both peptidomimetic and nonpeptide drug discovery has
been significant over the past few years. The integration of sophisticated computational chemical
technologies, structural biology (x-ray crystallography and NMR spectroscopy), molecular diversity and
high-through-put screening, and targeted biological testing are expected to provide invaluable guidance
to drug discovery. These “technological tools” are contributing to an emerging “3D structure-activity
database” that is the essence of rational drug design. Certainly, this intriguing area of peptidomimetic
and nonpeptide drug discovery and design is providing tremendous insight to our understanding of
molecular recognition and biochemical mechanisms. With particular regard to molecular diversity, the
generation of new leads from combinatorial chemistry focused on synthetic peptide, peptidomimetic, or
nonpeptide-type libraries will provide new opportunities (and challenges) for structure-based drug
design strategies (for reviews see Reference 276). Novel scaffolds and templates will continue to be
advanced and iteratively modified using “randomized” or “targeted” substructural replacements, and
such work is exemplified in this review. Of particular significance to the field of peptidomimetic and
nonpeptide drug discovery will be the rational use of D-amino acids, Nα-alkyl or Cα-alkyl amino acids,
N-substituted Gly, XxxΨ[Z]Yyy (dipeptide isosteres), benzodiazepines, and amino-benzoic acids in
structure-based drug design. Without question, structure-based drug design will be a decisive factor in
drug discovery efforts ranging from de novo design to iterative structural optimization of
peptidomimetic and nonpeptide lead compounds.
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