Identification and validation of novel pharmacological concepts
The identification of a novel mechanism that allows the pharmacological manipulation of human biology in a therapeutically useful manner is a very rare and transforming event in drug discovery. One systematic approach towards this goal involves gathering data from human patients that support the role of a protein in the pathology of the disease (a process called target identification). This can be the elucidation of altered signaling pathways at the cellular level or the identification of risk genes that are associated with the disease. At this stage animal models such as genetically engineered mice are often used to validate the role of the target protein in disease-relevant mammalian biology (target validation). It is then necessary to deduce a chemically tractable and functionally relevant binding site on the target protein. For intracellular proteins acting via protein or DNA interactions the latter step often poses a limiting barrier to the drug discovery process. Finally, it is necessary to identify a chemical starting point for the target protein. This molecule (e.g. a hit from a screening campaign) is then optimized by medicinal chemistry to a clinical candidate that has all the required properties for testing the therapeutic hypothesis in humans.
A goal of our lab is to identify novel chemically tractable protein targets and to provide the first ligands to allow validation of the pharmacological concept in animal models.