The spectrum of prospective drug targets under investigation in our laboratory is diverse and growing continuously:
• Protein Kinases (Wee-like kinases, CDKs, Aurora kinases, MST3, JAK2, Rock1, PLK1, TSSKs)
• Bromodomains (BET and other bromodomain families)
• Metabolic Enzymes (ALDH, LDH)
• Receptor Proteins (RAR, RXR, and Folate Receptors)
We generally follow two routes towards the discovery of novel inhibitors; both these approaches become interconnected if the target protein can be crystallized. The empirical approach involves the development of an assay suitable for high-throughput screening (HTS) of hundreds of thousands of small organic compounds for inhibitory activity. Thus discovered inhibitors (hits) will be scrutinized by structure-activity relationship (SAR) and kinetic studies until the most potent inhibitors with drug-like properties (leads) have been identified. The second route is the rational design of inhibitors based on the 3D atomic structure of the target protein. First, crystallization conditions suitable for reproducible growth of X-ray quality crystals need to be established. Then, the atomic structure of the target protein will be solved by crystallographic methods, bound with ligands such as substrates, known inhibitors or newly discovered HTS hits and leads. With this information in hand, we perform several computational studies (in silico design), such as molecular docking, to identify chemical scaffolds that satisfy the criteria for high inhibitory potential. During the entire inhibitor discovery process we closely collaborate with researchers of various disciplines, from synthetic organic chemistry to cell biology, to devise strategies for the optimization of the best inhibitors with respect to drug-like properties.