Do enthalpy and entropy distinguish first in class from best in class?
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Updated: Jul 2, 2026

Differential Scanning Calorimetry — A Method for Assessing the Thermal Stability and Conformation of Protein Antigen
Published on: March 4, 2017
1Department of Biology, Johns Hopkins University, Baltimore, MD 21218, United States. ef@jhu.edu
Abstract:
A drug molecule should bind to its target with high affinity and selectivity. Because the binding affinity is a combined function of the binding enthalpy and the binding entropy, extremely high affinity requires that both terms contribute favorably to binding. The binding enthalpy, however, is notoriously more difficult to optimize than the binding entropy, a fact that has resulted in thermodynamically unbalanced molecules that do not achieve optimal potency. In fact, with current technologies, the enthalpic optimization of drug candidates may take years and only appear in second-generation products. Within that context, it is not surprising that structure/activity relationships (SARs) that explicitly incorporate the interplay between enthalpy and entropy and accelerate the optimization process are being developed and gaining popularity.
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