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J Chem Inf Model. 2018 Sep 24;58(9):1976-1989. doi: 10.1021/acs.jcim.8b00185. Epub 2018 Sep 4.

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

Author information

1
Medicinal Chemistry , Monash Institute of Pharmaceutical Sciences, Monash University , Parkville , Victoria 3052 , Australia.
2
University Grenoble Alpes, CNRS, CERMAV , 38000 Grenoble , France.
3
University Grenoble Alpes, CNRS, DPM , 38000 Grenoble , France.
4
Chemical Biology of Carbohydrates , Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research , D-66123 Saarbrücken , Germany.
5
Deutsches Zentrum für Infektionsforschung (DZIF) , Standort Hannover-Braunschweig , Germany.
6
Department of Pharmacy , Saarland University , D-66123 Saarbrücken , Germany.
7
School of Science , RMIT University , Bundoora , Victoria 3083 , Australia.
8
Department of Surgery Austin Health , University of Melbourne , Heidelberg , Victoria 3084 , Australia.
9
Department of Immunology , Monash University, Alfred Medical Research and Education Precinct , Melbourne , Victoria 3004 , Australia.
10
Burnet Institute , Melbourne , Victoria 3004 , Australia.

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 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.

PMID:
30075071
DOI:
10.1021/acs.jcim.8b00185
[Indexed for MEDLINE]

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