Enthalpy-Entropy compensation is a ubiquitous phenomenon in protein-ligand binding. In lead optimizations, enthalpically favorable structural modifications are commonly associated with entropic penalties that negate the improvements in the binding affinity which would otherwise be gained due to the enthalpic benefits. Enthalpy-entropy compensation, therefore, renders many lead optimization cycles futile, and consequently, increases the time and the cost of drug discovery (i.e. an adversary phenomenon). Can we get anything good out of this adversary phenomenon? In this study, binding thermodynamic data of a series of thermolysin inhibitors that demonstrate remarkable enthalpy-entropy compensation are presented. Analysis of these data, however, can unexpectedly lead to a novel approach that can be used to improve protein-ligand binding. We herein describe this approach and how to apply it in the practice of medicinal chemistry.

Enthalpy-entropy compensation in protein-ligand binding: An adversary phenomenon that can lead to a novel strategy in drug design

248th National Meeting (2014)

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