Design and synthesis of type-III mimetics of omega-conotoxin GVIA.
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, omega-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.
Baell
J B
JB
Biomolecular Research Institute, Parkville, Victoria, Australia. jbaell@wehi.edu.au
Forsyth
S A
SA
Gable
R W
RW
Norton
R S
RS
Mulder
R J
RJ
D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry; D001665:Binding Sites; D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry; D020864:Calcium Channels, N-Type / Q000737:chemistry / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D018716:Molecular Mimicry; D011487:Protein Conformation; D020866:omega-Conotoxin GVIA / Q000737:chemistry*
D000700:Analgesics; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D020866:omega-Conotoxin GVIA