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Document Figure 8 Receptor-targeted peptidomimetics exemplifying ligand structure based drug design http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_572.html [4/9/2004 1:08:54 AM] Page 572
Document Figure 9 Peptide scaffold- and nonpeptide template-based design strategies: gpIIb/IIIa antagonists Page 573 peptidomimetic 37 was found to be a moderately potent SRIF-like agonist (partial) in cellular assays [41]. This discovery extends previous studies on TRH (see peptidomimetic 30, Figure 8) which utilized a cyclohexane ring system as a nonpeptide template to functionalize with the pyroglutamic acod and His side chains as well as the C-terminal carboxamide group of the parent peptide ligand [13]. However, in the comparative analysis of analogs of the SRIF-mimetic 37 it was also found that N-acetylation of the Lys side chain moiety yielded a potent antagonist of substance-P (NK 1 receptor). This indicated that slightly different functionalization of the nonpeptidic glucopyranoside template was quite compatible with NK 1 receptor molecular recognition. Intuitively, a “reversed design” strategy to convert the latter glucopyranoside-based NK 1 ligand to a cyclic peptide was next investigated (Figure 10), and successfully led to the discovery of a novel cyclic peptide ligand also exhibiting potent NK 1 receptor binding and antagonism [46]. The above examples of peptide scaffold- or nonpeptide template-based peptidomimetic agonists or antagonists illustrate various strategies to elaborate bioactive conformation and/or pharmacophore models of peptide ligands at their receptors. In many cases, receptor subtype selectivity has also been achieved by systematic structural modifications of prototypic leads of peptidomimetics. Thus, although the 3D structures of G-protein-coupled receptors (GPCRs) remain as elusive (except for models constructed from homology-based low- http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_573.html (1 of 2) [4/9/2004 1:09:25 AM]
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Document 2 Structural Studies of HI
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Document dine) and didanosine (dide
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Document Table 1 Inhibition Data fo
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Document References 1. Parks RE Jr.
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Document 6 Structural Implications
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Document Important for the validity
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Document Figure 4 Amino acids impor
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Page 693 and 694: Document structure. 2. Ligand probe
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Page 707 and 708: Document Page 569 molecule. A nonco
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Page 739 and 740: Document Figure 22 Protease 3D stru
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Page 743 and 744: Document Page 603 hydroxymethyl sub
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Document D ddI, 152 tumour necrosis
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Document [Protease targets] serinyl
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