SH3 Protein Domains and their Ligands

Abstract

Publication Number: WO/2003/013523 International Application No.: PCT/AU2002/001064 The present invention relates generally to molecules capable of interaction with one or more domains within a proteinaceous molecule such as a peptide, polypeptide, protein or a macromolecule comprising a proteinaceous molecule. More particularly the present invention relates to molecules including ligands which are capable of interacting with, and more particularly, binding to, SH3 protein domains or homologs thereof and even more particularly to molecules including ligands which are capable of binding to SH3 domains having a three-dimensional ligand-binding site comprising a negatively charged residue and a hydrophobic residue linearly separated by at least five amino acid residues. The subject invention is preferably directed to the use of 2-aminopyridine, 2-aminoquinoline, 1-aminoisoquinoline and derivatives, homologs, analogs and mimetics thereof or pharmaceutically acceptable salts thereof which interact with SH3 domains, and more particularly to the binding of 2-aminopyridine, 2-aminoquinoline, 1-aminoisoquinoline and derivatives analogs and mimetics to SH3 domains as defined above. The present invention contemplates the use of a three dimensional structure of the subject SH3 domain to identify, screen and design amino-substituted and amino-substituted pyridines and aminoquinolines capable of binding to an SH3 domain. The present invention is also useful for the in silico selection of derivatives homologs, analogs and mimetics of 2-aminopyridine, 2-aminoquinoline, 1-aminoisoquinoline capable of binding to SH3 domains. The ligands of the present invention are useful in the development of a range of therapeutic and diagnostic agents.