工具箱
计算生物学
虚拟筛选
抗生素
限制
化学
药物发现
组合化学
生物化学
立体化学
生物
计算机科学
机械工程
工程类
程序设计语言
作者
Ludvik Olai Espeland,C. Georgiou,Raphael Klein,Hemalatha Bhukya,Bengt Erik Haug,Jarl Underhaug,Prathama S. Mainkar,Ruth Brenk
出处
期刊:ChemMedChem
[Wiley]
日期:2021-08-06
卷期号:16 (17): 2715-2726
被引量:4
标识
DOI:10.1002/cmdc.202100302
摘要
FabF (3-oxoacyl-[acyl-carrier-protein] synthase 2), which catalyses the rate limiting condensation reaction in the fatty acid synthesis II pathway, is an attractive target for new antibiotics. Here, we focus on FabF from P. aeruginosa (PaFabF) as antibiotics against this pathogen are urgently needed. To facilitate exploration of this target we have set up an experimental toolbox consisting of binding assays using bio-layer interferometry (BLI) as well as saturation transfer difference (STD) and WaterLOGSY NMR in addition to robust conditions for structure determination. The suitability of the toolbox to support structure-based design of FabF inhibitors was demonstrated through the validation of hits obtained from virtual screening. Screening a library of almost 5 million compounds resulted in 6 compounds for which binding into the malonyl-binding site of FabF was shown. For one of the hits, the crystal structure in complex with PaFabF was determined. Based on the obtained binding mode, analogues were designed and synthesised, but affinity could not be improved. This work has laid the foundation for structure-based exploration of PaFabF.
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