Design and synthesis of type-III mimetics of omega-conotoxin GVIA |
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Authors: | Baell J B Forsyth S A Gable R W Norton R S Mulder R J |
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Affiliation: | (1) Biomolecular Research Institute, 343 Royal Parade, Parkville, Victoria, 3052, Australia;(2) School of Chemistry, University of Melbourne, Parkville, Victoria, 3052, Australia;(3) CSIRO Molecular Science, Bayview Avenue, Clayton, Victoria, 3168, Australia |
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Abstract: | Our interest lies in the rational design and synthesis of type-III mimetics of protein and polypeptide structure and function. Our approach involves interactive design of conformationally defined molecular scaffolds that project certain functional groups in a way that mimics the projection of important binding residues as determined in the parent structure. These design principles are discussed and applied to the structurally defined polypeptide, -conotoxin GVIA, which blocks voltage-gated, neuronal N-type calcium channels. These ion channels represent therapeutic targets for the development of new analgesics that can treat chronic pain. It is shown how a discontinuous, 3-residue pharmacophore of GVIA can be mimicked by different molecular scaffolds. It is illustrated how such 1st generation leads must necessarily be weak and that optimisability must therefore be built-in during the design process. |
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Keywords: | /content/8jgba8nldquf4t77/xxlarge969.gif" alt=" ohgr" align=" BASELINE" BORDER=" 0" >-Conotoxin GVIA ion channel blockers mimetics N-type calcium channel peptidomimetics proteinomimetics |
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