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dc.contributor.authorKersten, Christianen_US
dc.contributor.authorFleischer, Edmonden_US
dc.contributor.authorKehrein, Josefen_US
dc.contributor.authorBorek, Christophen_US
dc.contributor.authorJaenicke, Elmaren_US
dc.contributor.authorSotriffer, Christophen_US
dc.contributor.authorBrenk, Ruthen_US
dc.date.accessioned2020-06-15T07:56:04Z
dc.date.available2020-06-15T07:56:04Z
dc.date.issued2020
dc.PublishedKersten C, Fleischer E, Kehrein J, Borek C, Jaenicke E, Sotriffer C, Brenk R. How To Design Selective Ligands for Highly Conserved Binding Sites: A Case Study Using N-Myristoyltransferases as a Model System. Journal of Medicinal Chemistry. 2020;63(5):2095–2113eng
dc.identifier.issn1520-4804
dc.identifier.issn0022-2623
dc.identifier.urihttps://hdl.handle.net/1956/22581
dc.descriptionUnder embargo until: 2020-08-19en_US
dc.description.abstractA model system of two related enzymes with conserved binding sites, namely N-myristoyltransferase from two different organisms, was studied to decipher the driving forces that lead to selective inhibition in such cases. Using a combination of computational and experimental tools, two different selectivity-determining features were identified. For some ligands, a change in side-chain flexibility appears to be responsible for selective inhibition. Remarkably, this was observed for residues orienting their side chains away from the ligands. For other ligands, selectivity is caused by interfering with a water molecule that binds more strongly to the off-target than to the target. On the basis of this finding, a virtual screen for selective compounds was conducted, resulting in three hit compounds with the desired selectivity profile. This study delivers a guideline on how to assess selectivity-determining features in proteins with conserved binding sites and to translate this knowledge into the design of selective inhibitors.en_US
dc.language.isoengeng
dc.publisherACSeng
dc.titleHow To Design Selective Ligands for Highly Conserved Binding Sites: A Case Study Using N-Myristoyltransferases as a Model Systemen_US
dc.typePeer reviewed
dc.typeJournal article
dc.date.updated2019-11-08T16:33:09Z
dc.description.versionacceptedVersionen_US
dc.rights.holderCopyright 2019 American Chemical Society
dc.identifier.doihttps://doi.org/10.1021/acs.jmedchem.9b00586
dc.identifier.cristin1745529
dc.source.journalJournal of Medicinal Chemistry


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