Isothermal titration calorimetry in drug discovery

Area of Science:

• Biochemistry
• Biophysical Chemistry
• Structural Biology

Background:

• Isothermal titration calorimetry (ITC) is a biophysical technique.
• It measures heat changes associated with molecular binding events.
• ITC provides direct and facile interpretation of binding thermodynamics.

Purpose of the Study:

• To highlight the utility of ITC in characterizing protein-ligand interactions.
• To emphasize ITC's role in structure-based drug design and SAR studies.
• To explain the interpretation of binding enthalpy (ΔH°) and its implications.

Main Methods:

• Direct measurement of heat changes during molecular binding using ITC.
• Titration in the presence of other ligands to probe binding mechanisms.
• Characterization of protein fragments and mutant enzymes.

Main Results:

• ITC precisely quantifies binding affinity and stoichiometry.
• It directly measures the enthalpy of binding (ΔH°), offering insights into proton movement and ionization.
• ΔH° can reveal modified binding modes or protein conformational changes, indicating potential discontinuities in structure-activity relationships (SAR).

Conclusions:

• ITC is a powerful tool for characterizing protein-ligand interactions and binding thermodynamics.
• The direct measurement of ΔH° provides unique information complementary to affinity measurements.
• ITC data, especially ΔH°, can guide molecular design by highlighting critical binding events and SAR trends.