Hit Identification and Binding Mode Predictions by Rigorous Free Energy Simulations

Julien Michel, Jonathan W. Essex

Research output: Contribution to journalArticlepeer-review


The identification of lead molecules using computational modeling often relies on approximate, high-throughput approaches, of limited accuracy. We how here that, with a methodology we recently developed, it is possible to predict the relative binding free energies of structurally diverse ligands of the estrogen receptor-a using a rigorous statistical thermodynamics approach. Predictions obtained from the simulations with an explicit solvation model are in good qualitative agreement with experimental data, while simulations with implicit solvent models or rank ordering by empirical scoring functions yield predictions of lower quality. In addition, it is shown that free energy techniques can be used to select the most likely binding mode from a set of possible orientations generated by a docking program. It is Suggested that the free energy techniques outlined in this study can be used to rank-order, by potency, structurally diverse compounds identified by virtual screening, de novo design or scaffold hopping programs.

Original languageEnglish
Pages (from-to)6654-6664
Number of pages11
JournalJournal of Medicinal Chemistry
Issue number21
Publication statusPublished - 13 Nov 2008


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