Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476, Potsdam, Germany.
Department of Chemistry and Biochemistry, Freie Universität Berlin, Arnimallee 22, 14195, Berlin, Germany.
Angew Chem Int Ed Engl. 2022 Jan 3;61(1):e202109339. doi: 10.1002/anie.202109339. Epub 2021 Nov 23.
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 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 HA 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.
碳水化合物结合蛋白（凝集素）是药物发现中对抗抗微生物药物耐药性的有希望的靶点；然而，它们的非碳水化合物类似物药物抑制剂仍然不可用。在这里，我们提出了 Burkholderia ambifaria 中的一种 β-螺旋桨凝集素 BambL 中的一个可成药口袋，作为变构抑制剂的潜在靶标。该位点是通过 F NMR 片段筛选和计算口袋预测算法 SiteMap 来确定的。结构-活性关系研究揭示了最有前途的片段，其解离常数为 0.3±0.1 mM，配体效率为 0.3 kcal/molHA，影响了正位结合位点。这种效应通过在正位和次级口袋中的定点突变得到了证实。未来旨在开发小分子抑制剂的药物发现活动可以从凝集素的变构位点中受益，将其作为对抗抗药性病原体的新治疗方法。
