The design and synthesis of novel structural platforms which can project substituents into multiple regions of the receptor space is an important goal in the search for new leads for the discovery of molecular probes and eventually drugs. The proposed research intends to investigate the versatility of organometallic and inorganic compounds as structural scaffolds for the design of specific enzyme inhibitors. Such metal-ligand assemblies will allow convergent and economical synthetic approaches and will give access to structural motifs that differ from purely organic molecules. The specific goal of this research program encompasses the development of inert metal complexes that target the ATP-binding site of protein kinases. ATP-competitive inhibitors generally reach into the adenine binding pocket and form hydrogen bonds with the peptide backbone. Metal complexes with one ligand that bears the main structural features of one of these scaffolds can copy their mode of action. Additional ligands in the coordination sphere of the metal are intended to undergo specific contacts with other parts of the active site. Main focus will be the transformation of the class of indolocarbazole and indirubin inhibitors into metal complex scaffolds. This project includes the design and synthesis of adenine pocket-binding chelate ligands, the synthesis and examination of metal complexes, rational inhibitor design by molecular modeling, x-ray crystallographic studies of protein kinase domains in complex with metal compounds, structure-activity relationships, and combinatorial chemistry with metal complexes. The project bridges the fields of organic and inorganic medicinal chemistry by using metal centers as chemically inert structural scaffolds for drug design. This novel approach might lead to a new class of therapeutics.
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