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Document Page 560 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 http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_560.html [4/9/2004 12:53:53 AM]
Document Figure 1 Examples of native peptide hormones, neurotransmitters, and releasing factors Page 561 [9]. Finally, with respect to N-substituted amides it is also noteworthy to mention the intriguing approach [21] of replacing the traditional peptide scaffold by achiral N-substituted glycine building blocks. Overall, such Nα-Cα-C scaffold or Cα-Cβ side chain modifications provide significant opportunities for expanding peptide-based molecular diversity (i.e., so-called “peptoid” libraries) as well as to extend our 3D structural knowledge of traditional φ-Ψ-χ space. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_561.html (1 of 2) [4/9/2004 12:57:49 AM]
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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 Cyclotheonamide A (CtA), 2
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Document D ddI, 152 tumour necrosis
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Document antistasin peptides, 281 c
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