Drug Discovery & Development

Application Note

Conference Review

Target Validation

After a drug target has been identified, a rigorous evaluation needs to occur to demonstrate that modulation of the target will have the desired therapeutic effect.  This involves intensive in vitro, as well as in vivo studies that provide information on the effects of the pharmacological intervention.  The result of these efforts is to establish sufficient knowledge so that physiologically relevant model systems can be developed into assays for downstream screening.  This can have a significant impact on reducing the attrition rate of drug candidates due to clinical failures.

Isothermal Titration Calorimetry (ITC) can play a critical role in the determination of the mechanism of action (MOA) of a specified target pathway.  No prior knowledge of the biological process is required and there is no requirement for labeling or immobilization. Biomolecular interactions or reactions can be monitored in their natural state, often with endogenous enzymes, substrates or ligands.  This has the added benefit of dramatically reducing the assay development time.

Entire binding mechanisms can be systematically characterized.  For example, comparison of ligand binding can be made in all phases of the catalytic process with free enzyme, enzyme-substrate complex, or enzyme product, whether the enzyme is active or non-active. This can give a true picture of competitive, noncompetitive, and uncompetitive ligand binding.