Small molecule designed to target metal binding site in the α2I domain inhibits integrin function

Integrin alpha 2 beta 1 is a potential target molecule in drug development. We have established design criteria for molecules that bind to the closed conformation of alpha 2I domain via Mg2+ in MIDAS (metal ion dependent adhesion site) while simultaneously forming interactions with neighboring amino acid residues. Specific tetracyclic Streptomyces products belonging to the group of aromatic polyketides fulfill our criteria and inhibit alpha 2 beta 1 integrin. All previously described inhibitors of alpha I domain integrins act in an allosteric manner.