Abstract
A comprehensive characterization of the thermodynamic and kinetic profiling of ligands binding to a given target protein is crucial for the hit selection as well as the hit-to-lead-to-drug evolution. Isothermal titration calorimetry (ITC), widely known as an invaluable tool to measure the thermodynamic data, has recently found its way to determine the binding kinetics too. The extensive application of ITC in measurement of both thermodynamic and kinetic data manifests unique roles of ITC in drug discovery and development. This mini-review concentrates on elaborating how to gain the thermodynamic and kinetic data using ITC, highlighting the importance of these data in lead discovery and optimization, and intends to provide an overview of the technical and conceptual advances that offer unprecedented access to protein–ligand recognition by ITC measurement.
Highlights
Thermodynamic and kinetic profiles of ligand–protein association have reawakened interest in drug discovery since they provide mechanistic insights into the molecular interactions determining the affinity of a ligand to its target and are useful to guide the compound selection as well as the subsequent potency enhancement in the hit-to-lead-to-drug optimization (Olsson et al, 2008; Wang et al, 2017; Linkuviene et al, 2018)
Isothermal titration calorimetry is becoming an indispensable tool with the ability of determining the thermodynamic as well as kinetic parameters associated with protein–ligand recognition, playing a pronounced role in drug design
The thermodynamic profiling alone can provide information for hit selection and hit-to-lead optimization, when combined with the high-resolution complex structures, it will give us sufficient knowledge on the inherent factors determining the binding affinity and will provide deep insight into how the unpredictable water molecules, in particular those in the pocket, influence the protein– ligand binding event
Summary
Thermodynamic and kinetic profiles of ligand–protein association have reawakened interest in drug discovery since they provide mechanistic insights into the molecular interactions determining the affinity of a ligand to its target and are useful to guide the compound (hit or lead) selection as well as the subsequent potency enhancement in the hit-to-lead-to-drug optimization (Olsson et al, 2008; Wang et al, 2017; Linkuviene et al, 2018). It is not difficult to understand that longer residence time would allow the target remain the affected state even when the concentration of the drug has decreased. This is the major advantage of the drugs covalently binding to their targets as they have very long or even permanent residence time (Swinney, 2004; Zhang and Monsma, 2010)
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