Higher throughput calorimetry: opportunities, approaches and challenges

Area of Science:

• Biophysical Chemistry
• Structural Biology
• Drug Discovery and Development

Background:

• Higher throughput thermodynamic measurements are valuable in structure-based drug discovery, including fragment screening, hit validation, and lead optimization.
• Enthalpy measurements offer a sensitive method for detecting and characterizing ligand binding, sometimes revealing interaction changes more readily than free-energy changes or structural data.
• Current drug discovery processes are incorporating newer, higher throughput calorimeters.

Purpose of the Study:

• To evaluate the role and potential of higher throughput thermodynamic measurements in structure-based drug discovery.
• To compare the advancements and limitations of current calorimetric technologies, specifically titration calorimeters and emerging array calorimetry.
• To highlight the need for improved sensitivity in array calorimetry for its wider adoption.

Main Methods:

• Review and analysis of higher throughput thermodynamic measurement techniques, focusing on calorimetry.
• Comparison of established titration calorimetry with emerging array calorimetry.
• Assessment of the utility of enthalpy measurements in understanding protein-ligand interactions.

Main Results:

• Higher throughput thermodynamic measurements, especially enthalpy, provide critical insights into ligand binding during various stages of drug discovery.
• Improvements in titration calorimeters, while based on mature technology, face scaling limitations.
• Array calorimetry presents a promising emerging technology for significantly enhancing throughput and material efficiency, though sensitivity improvements are necessary.

Conclusions:

• Thermodynamic measurements, particularly enthalpy, are essential tools for structure-based drug discovery, complementing structural and free-energy data.
• While titration calorimeters offer incremental improvements, array calorimetry holds greater potential for future high-throughput applications.
• Further development is needed to enhance the sensitivity of array calorimetry to fully realize its benefits in drug discovery workflows.