A thermodynamic approach to the affinity optimization of drug candidates

Ernesto Freire

Research output: Contribution to journalArticlepeer-review

108 Scopus citations


High throughput screening and other techniques commonly used to identify lead candidates for drug development usually yield compounds with binding affinities to their intended targets in the mid-micromolar range. The affinity of these molecules needs to be improved by several orders of magnitude before they become viable drug candidates. Traditionally, this task has been accomplished by establishing structure activity relationships to guide chemical modifications and improve the binding affinity of the compounds. As the binding affinity is a function of two quantities, the binding enthalpy and the binding entropy, it is evident that a more efficient optimization would be accomplished if both quantities were considered and improved simultaneously. Here, an optimization algorithm based upon enthalpic and entropic information generated by Isothermal Titration Calorimetry is presented.

Original languageEnglish (US)
Pages (from-to)468-472
Number of pages5
JournalChemical Biology and Drug Design
Issue number5
StatePublished - Nov 2009


  • Binding affinity
  • Enthalpy
  • Entropy
  • Isothermal titration calorimetry
  • Thermodynamic optimization

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry


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