Shanina E.Kuhaudomlarp S.Lal K.Seeberger P.H.Imberty A.Rademacher C.Mahidol University2023-06-182023-06-182022-01-03Angewandte Chemie - International Edition Vol.61 No.1 (2022)14337851https://repository.li.mahidol.ac.th/handle/20.500.14594/84215Carbohydrate-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.ChemistryArticleSCOPUS10.1002/anie.2021093392-s2.0-8511968246115213773