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

Jonathan B. Baell, Stewart A. Forsyth, Robert W. Gable, Raymond S. Norton, Roger J. Mulder

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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.

Original languageEnglish
Pages (from-to)1119-1136
Number of pages18
JournalJournal of Computer-Aided Molecular Design
Volume15
Issue number12
DOIs
Publication statusPublished - 2001
Externally publishedYes

Keywords

  • ω-conotoxin GVIA
  • Ion channel blockers
  • Mimetics
  • N-type calcium channel
  • Peptidomimetics
  • Proteinomimetics

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