Thermal unfolding methods, applied in both isolated protein and cell-based settings, are increasingly used to identify and characterize hits during early drug discovery. Technical developments over recent years have facilitated their application in high-throughput approaches, and they now are used more frequently for primary screening. Widespread access to instrumentation and automation, the ability to miniaturize, as well as the capability and capacity to generate the appropriate scale and quality of protein and cell reagents have all played a part in these advances. As the nature of drug targets and approaches to their modulation have evolved, these methods have broadened our ability to provide useful chemical start points. Target proteins without catalytic function, or those that may be difficult to express and purify, are amenable to these methods. Here, we provide a review of the applications of thermal unfolding methods applied in hit finding during early drug discovery.
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