High affinity and selectivity are two essential properties of drug molecules.  Since the binding affinity is determined by the sum of enthalpic and entropic contributions, extremely high affinity necessitates optimization of both contributions to binding.  An efficient approach requires accurate prediction of the contributions of specific interactions and chemical functionalities to the enthalpy and entropy of binding. Selectivity has been difficult to achieve, especially for targets that belong to large families of structurally and functionally related proteins.  There are essentially two ways of improving selectivity during lead optimization: 1) introducing chemical modifications that improve affinity towards the target to a higher extent than to off target molecules; and, 2) introducing chemical modifications that actually lower affinity towards off target molecules.  Maximal selectivity is achieved when both conditions apply simultaneously.  Accurate thermodynamic rules derived from the affinity and selectivity optimization of protease inhibitors will be discussed.

Thermodynamic rules to achieve high affinity and selectivity

244th National Meeting (2012)

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