WG 1: Protein targets

Working Group Coordinator: Alberta Bergamo, Italy

Topic: Enzymes, or proteins in general, have evolved as important targets for metal-based drugs. Targeted proteins include - amongst others - protein kinases, receptors (surface and intracellular), histone deacetylases, and proteases. The anticipated modes of action of the metallo-drugs are extremely diverse and vary from target to target. Inhibiting an enzyme is often achieved by applying a metal complex that perfectly fits into a binding pocket of the protein, outcompeting the natural binding partner and thereby downregulating the enzyme's activity. In addition to this non-covalent interaction, coordinative bonds may be formed between a metal complex and amino acid residues in the active site of the target. Accordingly, such metal complexes have in common that their design is based on the knowledge of the three-dimensional structure of the binding site within the protein. In particular in the context of targeting proteins, metal complexes often excel traditional purely organic inhibitor compounds as a result of their extreme structural diversity. One approach applied by this WG for the development of metal-based inhibitors is closely related to well-established strategies in medicinal chemistry for organic compounds. For example, combinatorial chemistry followed by a screening will provide initial lead structures that will be used for obtaining a co-crystal structure of such a complex bound to the active site of the target and later will serve as a starting point for structure-based design. In addition, research towards the identification of the physiological (pathological) role of the identified proteins will be performed. Targeting proteins relevant for controlling or sustaining cell growth, cell survival and malignancy/virulence with metal-based drugs can be of extreme importance for controlling tumours or infectious diseases. Hence, within this WG, new protein targets for metal-based drugs will be identified, and metal complexes targeting these as well as established protein targets will be developed and evaluated.