Journal of Computer-Aided Molecular Design

, Volume 24, Issue 8, pp 639–658 | Cite as

Prediction of protein–ligand binding affinity by free energy simulations: assumptions, pitfalls and expectations

  • Julien MichelEmail author
  • Jonathan W. Essex


Many limitations of current computer-aided drug design arise from the difficulty of reliably predicting the binding affinity of a small molecule to a biological target. There is thus a strong interest in novel computational methodologies that claim predictions of greater accuracy than current scoring functions, and at a throughput compatible with the rapid pace of drug discovery in the pharmaceutical industry. Notably, computational methodologies firmly rooted in statistical thermodynamics have received particular attention in recent years. Yet free energy calculations can be daunting to learn for a novice user because of numerous technical issues and various approaches advocated by experts in the field. The purpose of this article is to provide an overview of the current capabilities of free energy calculations and to discuss the applicability of this technology to drug discovery.


Structure-based drug design Protein–ligand binding affinity Free energy calculations Molecular simulations 



This research was partially supported (J.M.) by a Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme (FP7-PEOPLE-2008-4-1-IOF, 234796-PPIdesign).


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Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  1. 1.Institute of Structural and Molecular BiologyThe University of EdinburghEdinburghUK
  2. 2.Department of ChemistryYale UniversityNew HavenUSA
  3. 3.School of ChemistryUniversity of SouthamptonHighfield, SouthamptonUK

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