Free energies of ligand binding for structurally diverse compounds

B.C. Oostenbrink, W.F. van Gunsteren

Research output: Contribution to JournalArticleAcademicpeer-review


The one-step perturbation approach is an efficient means to calculate many relative free energies from a common reference compound. Combining lessons learned in previous studies, an application of the method is presented that allows for the calculation of relative binding free energies for structurally rather diverse compounds from only a few simulations. Based on the well known statistical–mechanical perturbation formula, the results do not require any empirical parameters, or training sets, only limited knowledge of the binding characteristics of the ligands suffices to design appropriate reference compounds. Depending on the choice of reference compound, relative free energies of binding rigid ligands to the ligand-binding domain of the estrogen receptor can be obtained that show good agreement with the experimental values. The approach presented here can easily be applied to many rigid ligands, and it should be relatively easy to extend the method to account for ligand flexibility. The free-energy calculations can be straightforwardly parallelized, allowing for an efficient means to understand and predict relative binding free energies.
Original languageEnglish
Pages (from-to)6750-6754
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number19
Publication statusPublished - 10 May 2005


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