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Druggable Allosteric Sites in β‐Propeller Lectins

Carbohydrate‐binding proteins (lectins) are auspicious targets in drug discovery to combat antimicrobial resistance; however, their non‐carbohydrate drug‐like inhibitors are still unavailable. Here, we present a druggable pocket in a β‐propeller lectin BambL from Burkholderia ambifaria as a potentia...

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Autores principales: Shanina, Elena, Kuhaudomlarp, Sakonwan, Lal, Kanhaya, Seeberger, Peter H., Imberty, Anne, Rademacher, Christoph
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9298952/
https://www.ncbi.nlm.nih.gov/pubmed/34713573
http://dx.doi.org/10.1002/anie.202109339
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author Shanina, Elena
Kuhaudomlarp, Sakonwan
Lal, Kanhaya
Seeberger, Peter H.
Imberty, Anne
Rademacher, Christoph
author_facet Shanina, Elena
Kuhaudomlarp, Sakonwan
Lal, Kanhaya
Seeberger, Peter H.
Imberty, Anne
Rademacher, Christoph
author_sort Shanina, Elena
collection PubMed
description Carbohydrate‐binding proteins (lectins) are auspicious targets in drug discovery to combat antimicrobial resistance; however, their non‐carbohydrate drug‐like inhibitors are still unavailable. Here, we present a druggable pocket in a β‐propeller lectin BambL from Burkholderia ambifaria as a potential target for allosteric inhibitors. This site was identified employing (19)F NMR fragment screening and a computational pocket prediction algorithm SiteMap. The structure–activity relationship study revealed the most promising fragment with a dissociation constant of 0.3±0.1 mM and a ligand efficiency of 0.3 kcal mol(−1) HA(−1) that affected the orthosteric site. This effect was substantiated by site‐directed mutagenesis in the orthosteric and secondary pockets. Future drug‐discovery campaigns that aim to develop small molecule inhibitors can benefit from allosteric sites in lectins as a new therapeutic approach against antibiotic‐resistant pathogens.
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spelling pubmed-92989522022-07-21 Druggable Allosteric Sites in β‐Propeller Lectins Shanina, Elena Kuhaudomlarp, Sakonwan Lal, Kanhaya Seeberger, Peter H. Imberty, Anne Rademacher, Christoph Angew Chem Int Ed Engl Research Articles Carbohydrate‐binding proteins (lectins) are auspicious targets in drug discovery to combat antimicrobial resistance; however, their non‐carbohydrate drug‐like inhibitors are still unavailable. Here, we present a druggable pocket in a β‐propeller lectin BambL from Burkholderia ambifaria as a potential target for allosteric inhibitors. This site was identified employing (19)F NMR fragment screening and a computational pocket prediction algorithm SiteMap. The structure–activity relationship study revealed the most promising fragment with a dissociation constant of 0.3±0.1 mM and a ligand efficiency of 0.3 kcal mol(−1) HA(−1) that affected the orthosteric site. This effect was substantiated by site‐directed mutagenesis in the orthosteric and secondary pockets. Future drug‐discovery campaigns that aim to develop small molecule inhibitors can benefit from allosteric sites in lectins as a new therapeutic approach against antibiotic‐resistant pathogens. John Wiley and Sons Inc. 2021-11-23 2022-01-03 /pmc/articles/PMC9298952/ /pubmed/34713573 http://dx.doi.org/10.1002/anie.202109339 Text en © 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Research Articles
Shanina, Elena
Kuhaudomlarp, Sakonwan
Lal, Kanhaya
Seeberger, Peter H.
Imberty, Anne
Rademacher, Christoph
Druggable Allosteric Sites in β‐Propeller Lectins
title Druggable Allosteric Sites in β‐Propeller Lectins
title_full Druggable Allosteric Sites in β‐Propeller Lectins
title_fullStr Druggable Allosteric Sites in β‐Propeller Lectins
title_full_unstemmed Druggable Allosteric Sites in β‐Propeller Lectins
title_short Druggable Allosteric Sites in β‐Propeller Lectins
title_sort druggable allosteric sites in β‐propeller lectins
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9298952/
https://www.ncbi.nlm.nih.gov/pubmed/34713573
http://dx.doi.org/10.1002/anie.202109339
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