Free energy methods in ligand design

Yvonne Westermaier*, Roderick E. Hubbard

*Corresponding author for this work

Research output: Chapter in Book/Report/Conference proceedingChapter


This chapter gives an overview of currently available free energy (FE) methods to support the optimization of ligand binding to protein targets. The calculations provide insights into the physical chemistry of protein-ligand interactions and can be used as a practical tool to optimize initial hit compounds during drug discovery. After a broad introduction to these methods, the techniques are reviewed with particular emphasis on their use in the lead optimization (LO) phase of drug discovery. Besides providing examples which are of pharmaceutical interest, it also gives practical suggestions on the choice of an FE method and best practices.

Original languageEnglish
Title of host publicationDe novo Molecular Design
Number of pages43
ISBN (Electronic)9783527677016
ISBN (Print)9783527334612
Publication statusPublished - 11 Oct 2013


  • Free energy methods
  • Free energy perturbation
  • Lead optimization phase
  • Linear interaction energy
  • Potential of mean force
  • Thermodynamic integration
  • Virtual screening

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