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Compensating enthalpic and entropic changes hinder binding affinity optimization.

Virginie Lafont1, Anthony A Armstrong, Hiroyasu Ohtaka

  • 1Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA.

Chemical Biology & Drug Design
|June 22, 2007
PubMed
Summary
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Adding chemical groups to drug candidates can improve potency, but sometimes strong hydrogen bonds don't increase effectiveness. This study reveals the thermodynamic and structural reasons why enthalpy-entropy compensation limits drug potency.

Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Structural Biology

Background:

  • Drug discovery often involves adding functional groups to enhance target interactions and potency.
  • However, observed improvements in binding affinity do not always correlate with the formation of strong hydrogen bonds.

Purpose of the Study:

  • To investigate the thermodynamic and structural basis for the lack of potency improvement despite strong hydrogen bond formation in drug candidates.
  • To explore strategies for overcoming enthalpy-entropy compensation to enhance binding affinity.

Main Methods:

  • Thermodynamic analysis (isothermal titration calorimetry) of inhibitor-protease binding.
  • X-ray crystallography to determine the structural basis of binding.
  • Comparative analysis of KNI-10033 (thioether) and KNI-10075 (sulfonyl) HIV-1 protease inhibitors.

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Main Results:

  • KNI-10033 exhibits picomolar affinity for HIV-1 protease, driven by favorable enthalpy and entropy.
  • Replacing the thioether with a sulfonyl group in KNI-10075 forms a strong hydrogen bond, improving binding enthalpy by 3.9 kcal/mol.
  • This enthalpy gain is fully offset by an entropic penalty, resulting in no net change in binding affinity, attributed to conformational and solvation effects.

Conclusions:

  • Enthalpy-entropy compensation can negate the benefits of introducing hydrogen bond-forming groups.
  • Understanding conformational and solvation effects is crucial for designing potent inhibitors.
  • Provides guidelines to overcome enthalpy-entropy compensation for improved drug design.