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dc.contributor.authorDingjan, Tamir
dc.contributor.authorGillon, Émilie
dc.contributor.authorImberty, Anne
dc.contributor.authorPérez, Serge
dc.contributor.authorTitz, Alexander
dc.contributor.authorRamsland, Paul A
dc.contributor.authorYuriev, Elizabeth
dc.date.accessioned2019-10-11T12:03:03Z
dc.date.available2019-10-11T12:03:03Z
dc.date.issued2018-09-24
dc.identifier.citationJ Chem Inf Model. 2018 Sep 24;58(9):1976-1989. doi: 10.1021/acs.jcim.8b00185. Epub 2018 Sep 4en_US
dc.identifier.issn1549-960X
dc.identifier.pmid30075071
dc.identifier.doi10.1021/acs.jcim.8b00185
dc.identifier.urihttp://hdl.handle.net/10033/621973
dc.description.abstractBacterial adhesion to human epithelia via lectins constitutes a therapeutic opportunity to prevent infection. Specifically, BambL (the lectin from Burkholderia ambifaria) is implicated in cystic fibrosis, where lectin-mediated bacterial adhesion to fucosylated lung epithelia is suspected to play an important role. We employed structure-based virtual screening to identify inhibitors of BambL-saccharide interaction with potential therapeutic value. To enable such discovery, a virtual screening protocol was iteratively developed via 194 retrospective screening protocols against 4 bacterial lectins (BambL, BC2L-A, FimH, and LecA) with known ligands. Specific attention was given to the rigorous evaluation of retrospective screening, including calculation of analytical errors for enrichment metrics. The developed virtual screening workflow used crystallographic constraints, pharmacophore filters, and a final manual selection step. The protocol was applied to BambL, predicting 15 active compounds from virtual libraries of approximately 7 million compounds. Experimental validation using fluorescence polarization confirmed micromolar inhibitory activity for two compounds, which were further characterized by isothermal titration calorimetry and surface plasmon resonance. Subsequent testing against LecB from Pseudomonas aeruginosa demonstrated binding specificity of one of the hit compounds. This report demonstrates the utility of virtual screening protocols, integrating ligand-based pharmacophore filtering and structure-based constraints, in the search for bacterial lectin inhibitors.en_US
dc.language.isoenen_US
dc.publisherAmerican Chemical Societyen_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleVirtual Screening Against Carbohydrate-Binding Proteins: Evaluation and Application to Bacterial Burkholderia ambifaria Lectin.en_US
dc.typeArticleen_US
dc.contributor.departmentHIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.en_US
dc.identifier.journalJournal of Chemical Information and Modelingen_US
dc.source.journaltitleJournal of chemical information and modeling


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