| Optimizing the affinity of lead compounds is a critical step in drug research. Integrating 3D structural knowledge, thermodynamics and kinetics of ligand-receptor interactions offers a new approach in the drug design paradigm. It allows a thorough understanding of e.g. solvent effects, entropy effects, dynamics, and enthalpy-entropy compensation in drug-receptor interactions. All these effects can have large positive or negative contributions to the free binding energy, which can not be predicted by knowledge of the 3D-structure alone. The only technique to assay thermodynamics is microcalorimetry, which basically measures heat effects of molecular interactions. Studying series of structurally related compounds allows relating thermodynamic effects of the binding interaction to molecular properties, and this is guiding in optimization of ligand structures in design cycles. This type of research is well embedded, and at the core of the recent strategic choice for the major research focal point Drug Innovation, as well as the Chemical Biology Program, at Utrecht University. Top expertise in the fields of organic synthesis, X-ray crystallography, NMR, MS and SPR is available to link molecular sciences to therapeutics. High level biophysical equipment is available, however, for microcalorimetry there is only one obsolete ITC instrument in Utrecht. The requested instrument is the recently launched Auto ITC200 system from MicroCal, which has significantly increased sensitivity compared to the previous, successful VP series, and can be operated fully automated. |
