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Related Experiment Videos

The maximal affinity of ligands.

I D Kuntz1, K Chen, K A Sharp

  • 1Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143-0446, USA. kuntz@cgl.ucsf.edu

Proceedings of the National Academy of Sciences of the United States of America
|September 1, 1999
PubMed
Summary

The strongest molecular ligands binding to targets show binding energy increases with atom count initially. Beyond 15 atoms, binding energy gains diminish, influenced by non-thermodynamic factors and hydrophobic interactions.

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Peter Andrew Kollman.

Proteins·2001

Area of Science:

  • Drug discovery and medicinal chemistry
  • Biophysics and structural biology
  • Computational chemistry

Background:

  • Understanding ligand-macromolecular interactions is crucial for drug development.
  • Identifying optimal ligands requires analyzing binding affinity determinants.
  • Existing models may not fully capture the complexity of binding energy scaling.

Purpose of the Study:

  • To determine the characteristics of the most effective ligands for macromolecular targets.
  • To investigate the relationship between ligand properties and binding free energy.
  • To identify factors influencing ligand binding affinity.

Main Methods:

  • Survey of experimental binding data for numerous strong-binding ligands.
  • Analysis of the correlation between ligand size (nonhydrogen atoms) and binding free energy.

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  • Examination of dominant interaction types (van der Waals, hydrophobic effects).

    • Main Results:

    • Binding free energy increases with nonhydrogen atom count, with an initial slope of ~ -1.5 kcal/mol per atom.
    • For ligands >15 nonhydrogen atoms, binding energy gains plateau with increasing molecular mass.
    • Nonthermodynamic factors significantly impact this non-linear relationship.
    • Van der Waals forces and hydrophobic effects are key drivers of binding affinity.

    Conclusions:

    • Ligand efficiency plateaus beyond a certain size due to non-thermodynamic constraints.
    • Hydrophobic effects and van der Waals interactions are fundamental to ligand binding.
    • Specific outliers (metal ions, covalent ligands, biotin-avidin) demonstrate exceptionally strong binding per atom.