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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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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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. |
format | Online Article Text |
id | pubmed-9298952 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
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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