16. Free Energy Methods in Ligand Design

  1. Gisbert Schneider
  1. Yvonne Westermaier1,2 and
  2. Roderick E. Hubbard1,3

Published Online: 11 OCT 2013

DOI: 10.1002/9783527677016.ch16

De novo Molecular Design

De novo Molecular Design

How to Cite

Westermaier, Y. and Hubbard, R. E. (2013) Free Energy Methods in Ligand Design, in De novo Molecular Design (ed G. Schneider), Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany. doi: 10.1002/9783527677016.ch16

Editor Information

  1. ETH Zürich, Institute of Pharmaceutical Sciences, Wolfgang-Pauli-Strasse 10, 8093 Zürich, Switzerland

Author Information

  1. 1

    University of York, Department of Chemistry, YSBL, Heslington, York, YO10 5DD, UK

  2. 2

    Universitat de Barcelona, Facultat de Farmàcia, Departament de Fisicoquímica and Institut de Biomedicina, Computational Biology and Drug Design Group, Avinguda Joan XXIII, s/n, 08028 Barcelona, Spain

  3. 3

    Vernalis (R&D) Ltd, Granta Park, Cambridge, CB21 6GB, UK

Publication History

  1. Published Online: 11 OCT 2013
  2. Published Print: 13 NOV 2013

ISBN Information

Print ISBN: 9783527334612

Online ISBN: 9783527677016



  • free energy methods;
  • lead optimization phase;
  • virtual screening;
  • free energy perturbation;
  • potential of mean force;
  • linear interaction energy;
  • thermodynamic integration


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.