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dc.contributor.authorLee, Hui Sun
dc.contributor.authorJo, Sunhwan
dc.contributor.authorLim, Hyun-Suk
dc.contributor.authorIm, Wonpil
dc.date.accessioned2017-05-16T18:04:20Z
dc.date.available2017-05-16T18:04:20Z
dc.date.issued2012-01-23
dc.identifier.citationLee, H. S., Jo, S., Lim, H.-S., & Im, W. (2012). Application of Binding Free Energy Calculations to Prediction of Binding Modes and Affinities of MDM2 and MDMX Inhibitors. Journal of Chemical Information and Modeling, 52(7), 1821–1832. http://doi.org/10.1021/ci3000997en_US
dc.identifier.urihttp://hdl.handle.net/1808/24225
dc.description.abstractMolecular docking is widely used to obtain binding modes and binding affinities of a molecule to a given target protein. Despite considerable efforts, however, prediction of both properties by docking remains challenging mainly due to protein’s structural flexibility and inaccuracy of scoring functions. Here, an integrated approach has been developed to improve the accuracy of binding mode and affinity prediction, and tested for small molecule MDM2 and MDMX antagonists. In this approach, initial candidate models selected from docking are subjected to equilibration MD simulations to further filter the models. Free energy perturbation molecular dynamics (FEP/MD) simulations are then applied to the filtered ligand models to enhance the ability in predicting the near-native ligand conformation. The calculated binding free energies for MDM2 complexes are overestimated compared to experimental measurements mainly due to the difficulties in sampling highly flexible apo-MDM2. Nonetheless, the FEP/MD binding free energy calculations are more promising for discriminating binders from nonbinders than docking scores. In particular, the comparison between the MDM2 and MDMX results suggests that apo-MDMX has lower flexibility than apo-MDM2. In addition, the FEP/MD calculations provide detailed information on the different energetic contributions to ligand binding, leading to a better understanding of the sensitivity and specificity of protein-ligand interactions.en_US
dc.publisherAmerican Chemical Societyen_US
dc.rightsThis document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Chemical Information and Modeling, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://doi.org/10.1021/ci3000997.en_US
dc.subjectMolecular dynamics simulationen_US
dc.subjectFree energy perturbationen_US
dc.subjectProtein-protein interactionen_US
dc.subjectDockingen_US
dc.subjectComputer-aided drug designen_US
dc.titleApplication of Binding Free Energy Calculations to Prediction of Binding Modes and Affinities of MDM2 and MDMX Inhibitorsen_US
dc.typeArticleen_US
kusw.kuauthorJo, Sunhwan
kusw.kuauthorLee, Hui Sun
kusw.kuauthorIm, Wonpil
kusw.kudepartmentMolecular dynamicsen_US
dc.identifier.doi10.1021/ci3000997en_US
dc.identifier.orcidhttps://orcid.org/0000-0002-4104-6473
kusw.oaversionScholarly/refereed, publisher versionen_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US
dc.identifier.pmidPMC3480999en_US
dc.rights.accessrightsopenAccess


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