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

Author(s): Baell, JB; Forsyth, SA; Gable, RW; Norton, RS; Mulder, RJ;
Details: Publication Year 2001-12,Volume 15,Issue #12,Page 1119-1136
Journal Title: JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
Publication Type: Journal Article
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, 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 1(st) generation leads must necessarily be weak and that optimisability must therefore be built-in during the design process.
Publisher: KLUWER ACADEMIC PUBL
Keywords: CALCIUM-CHANNEL BINDING; FUNCTIONAL ASSAY; HOT-SPOT; PEPTIDE; RECEPTOR; INHIBITOR; ANALOGS; ANTAGONISTS; MUTAGENESIS; RECOGNITION
Publisher's Version: https://doi.org/10.1023/A:1015930031890
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2001-12-01 12:00:00