Nonpeptide molecules

Docking also provided insight into the 3D hydrophobic requirements for binding of nonpeptide molecules in the SH2 domain of ppGOsrc at ARIAD Pharmaceuticals [92]. 

Synthesis of constrained peptide sequences has now been followed by combinations of nonpeptide molecules. As greater constraints are introduced, the numerical productivity falls, but presumably the proportion of leads increases. 

The potential utility of peptides as therapeutic agents with clinical applications is limited as a consequence of intrinsic peptide properties such as metabolic instability or poor transmembrane mobility. Hence, the design and synthesis of meta-bolically stable peptide analogs that can either mimic or block the bioactivity of natural peptides or enzymes is an important area of medicinal chemistry research. Numerous structural modifications to peptides have been examined in pursuit of molecules with more desirable properties [1-3]. These modified structures, peptidomimetics, are nonpeptide molecules that imitate the desired properties of the natural substances. 

Sucholeiki I, Solid-phase photochemical C-S bond cleavage of thioethers—a new approach to the solid-phase production of nonpeptide molecules, Tetrahedron Lett., 35 7307-7310, 1994. 

The advantage of such a pharmocophore model is that smaller, nonpeptide molecules that might have improved stability and bioavailability over their peptidic counterparts... 

In addition to studies on toosendanin, there are a number of other efforts to develop natural products as BoNT inhibitors, most notably from the laboratory of Dr Bavari. Using the peptide-based inhibitor 2-mercapto-3-phenylpropionyl-RATKML developed by Schmidt and Stafford (2002), Burnett et al. (2007) examined the interaction of this molecule with the active site of BoNT/A LC. The investigators then screened small nonpeptide molecules from the National Cancer Institute s Open Repository and tested these for inhibitory activity using an HPLC assay and in chick spinal motor neurons. Several compounds were effective in the HPLC assay (/q = 3-10 JlM), and one, NSC 240898, was found to be effective in producing a concentration-dependent protection of SNAP-25 in cultured spinal cord cells with no evidence of toxicity up to 40 I M. 

Another critical question relates to the development of a pharmacology for neuronal Ca " channels. While L-type Ca " channels have a rich pharmacology that has provided novel therapeutic approaches to treat cardiovascular diseases, nonpeptide molecules, which block or inactivate the N, P, Q, T, or R channels, are lacking. Thus, a major goal for research in this field is the search for selective blockers or modulators of specific Ca " channel subtypes that could eventually be used as therapeutic tools in disease. The recent introduction of mibefradil as a T-type Ca " channel blocker opened new possibilities to study the functions of these channels. The knowledge of the three-dimensional structure in solution of the different toxins is very important for studying the specificity of their interactions with Ca " channel subtypes, and to define active sites that can... 

Investigations on calixarene-based pseudo-biomimetic catalyst has received considerable attention because calixarenes can be functionalized on this purpose, and particularly they are nonpeptidic molecules that mimic structural and substitution aspect of the biomolecules [35, 36]. In principle, calixarene-based pseudo-biocatalysts... 

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