Higher throughput calorimetry: opportunities, approaches and challenges

Abstract

Higher throughput thermodynamic measurements can provide value in structure-based drug discovery during fragment screening, hit validation, and lead optimization. Enthalpy can be used to detect and characterize ligand binding, and changes that affect the interaction of protein and ligand can sometimes be detected more readily from changes in the enthalpy of binding than from the corresponding free-energy changes or from protein-ligand structures. Newer, higher throughput calorimeters are being incorporated into the drug discovery process. Improvements in titration calorimeters come from extensions of a mature technology and face limitations in scaling. Conversely, array calorimetry, an emerging technology, shows promise for substantial improvements in throughput and material utilization, but improved sensitivity is needed.

A fast and reliable method for monitoring of prophage‐activating chemicals

“…Wadsö et al ., 2017), (ii) by the development of arrays of chip‐calorimeters (Torres et al ., 2010; Huynh et al ., 2015), and (iii) by the segmented fluid technology for a chip‐calorimeter. (Maskow et al ., 2011; Wolf et al ., 2015) Future research should aim to open up additional application areas.…”

The impact of binding thermodynamics on medicinal chemistry optimizations

“…Owing to their low affinity, compounds have to be screened at high concentration that requires high solubility. In line with their small size and polarity that allows fragments to form few, good quality polar interactions without significant contribution from apolar desolvation fragment hits typically bind with favorable enthalpy [17,30,31,32,33,34,35] ( Figure 5). The few compounds in Figure 5 that bind with unfavorable enthalpy are all anionic species with highly unfavourable desolvation profile.…”

“…The predominant experimental technic for measuring thermodynamic profiles is expected to remain isothermal titration calorimetry as it is able to provide G, H, and S in a single experiment for soluble proteins. The limitations of ITC measurements, namely throughput and the amount of protein required have been significantly alleviated by recent technological developments [65,35] and this is likely to increase the role of thermodynamic measurements both in hit identification and in optimization. This trend is expected to apply also for fragment based drug discovery since recent results have clearly demonstrated the feasibility of applying ITC in this domain [32,34,35].…”

Review of MEMS differential scanning calorimetry for biomolecular study

“…This can pose problems in cases where only minute sample quantities are available for testing. There has been a strong demand to develop high throughput and high sensitivity calorimeter for rapid detection of biomolecular interaction for decades [16][17][18][19]. The microfabrication and nanofabrication technologies allow the miniaturization of the conventional bench-top scale instrument for the building of micro/nano DSC with microfluidic embedded systems, micro temperature sensors and heaters [20].…”