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Design and synthesis of type-III mimetics of ω-conotoxin GVIA

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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, ω-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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Baell, J.B., Forsyth, S.A., Gable, R.W. et al. Design and synthesis of type-III mimetics of ω-conotoxin GVIA. J Comput Aided Mol Des 15, 1119–1136 (2001). https://doi.org/10.1023/A:1015930031890

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