Crystallographic screening for and hit expansion of P. aeruginosa FabF inhibitors – a possible starting point for novel antibiotics

A crystallographic fragment screen resulted in several FabF hits, binding to various pockets as well as the interface of the protein dimer. For two active site hits, a rudimentary hit expansion was carried out, exploring binding for the hits binding the malonyl sub-pocket. For the malonyl sub-pocket inhibitors, only weak affinity was observed, but the crystallographic data can conceivably guide future linking and merging strategies.

晶体学片段筛选获得了多个FabF结合片段（hits），这些片段可结合蛋白二聚体的多个口袋及界面区域。针对两个活性位点结合片段，研究人员开展了初步的片段扩展实验，探索了结合丙二酰亚口袋的片段的结合特性。对于丙二酰亚口袋抑制剂，仅观察到弱亲和力，但晶体学数据有望为未来的连接与融合策略提供指导。