Virtual Screening Against Carbohydrate-binding Proteins: Evaluation and Application to Bacterial Burkholderia ambifaria Lectin

Dingjan, T, Gillon, E, Imberty, A, Perez, S, Titz, A, Ramsland, P and Yuriev, E 2018, 'Virtual Screening Against Carbohydrate-binding Proteins: Evaluation and Application to Bacterial Burkholderia ambifaria Lectin', Journal of Chemical Information and Modeling, vol. 58, no. 9, pp. 1976-1989.


Document type: Journal Article
Collection: Journal Articles

Title Virtual Screening Against Carbohydrate-binding Proteins: Evaluation and Application to Bacterial Burkholderia ambifaria Lectin
Author(s) Dingjan, T
Gillon, E
Imberty, A
Perez, S
Titz, A
Ramsland, P
Yuriev, E
Year 2018
Journal name Journal of Chemical Information and Modeling
Volume number 58
Issue number 9
Start page 1976
End page 1989
Total pages 14
Publisher American Chemical Society
Abstract Bacterial 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 have employed structure-based virtual screening to identify inhibitors of BambL-saccharide interaction with potential therapeutic value. In order to enable such discovery, a virtual screening protocol has been iteratively developed via 194 retrospective screening protocols against four 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.
Subject Structural Biology (incl. Macromolecular Modelling)
Bacteriology
Medical Biochemistry: Carbohydrates
DOI - identifier 10.1021/acs.jcim.8b00185
Copyright notice © 2018 American Chemical Society
ISSN 1549-9596
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