Alchemical free energy methods for drug discovery: progress and challenges

Curr Opin Struct Biol. 2011 Apr;21(2):150-60. doi: 10.1016/ Epub 2011 Feb 23.


Improved rational drug design methods are needed to lower the cost and increase the success rate of drug discovery and development. Alchemical binding free energy calculations, one potential tool for rational design, have progressed rapidly over the past decade, but still fall short of providing robust tools for pharmaceutical engineering. Recent studies, especially on model receptor systems, have clarified many of the challenges that must be overcome for robust predictions of binding affinity to be useful in rational design. In this review, inspired by a recent joint academic/industry meeting organized by the authors, we discuss these challenges and suggest a number of promising approaches for overcoming them.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Computational Biology* / methods
  • Drug Design
  • Drug Discovery* / methods
  • Protein Binding
  • Proteins / chemistry
  • Proteins / metabolism


  • Proteins