Druggable Allosteric Sites in β-Propeller Lectins
Issued Date
2022-01-03
Resource Type
ISSN
14337851
eISSN
15213773
Scopus ID
2-s2.0-85119682461
Journal Title
Angewandte Chemie - International Edition
Volume
61
Issue
1
Rights Holder(s)
SCOPUS
Bibliographic Citation
Angewandte Chemie - International Edition Vol.61 No.1 (2022)
Suggested Citation
Shanina E., Kuhaudomlarp S., Lal K., Seeberger P.H., Imberty A., Rademacher C. Druggable Allosteric Sites in β-Propeller Lectins. Angewandte Chemie - International Edition Vol.61 No.1 (2022). doi:10.1002/anie.202109339 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/84215
Title
Druggable Allosteric Sites in β-Propeller Lectins
Other Contributor(s)
Abstract
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 19F 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.