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基于结构的铜绿假单胞菌 FabF 抑制剂发现的实验工具包，FabF 是一种有前景的抗生素靶标。

An Experimental Toolbox for Structure-Based Hit Discovery for P. aeruginosa FabF, a Promising Target for Antibiotics.

机构信息

Department of Biomedicine, University of Bergen, Jonas Lies Vei 91, 5020, Bergen, Norway.

Department of Chemistry, University of Bergen, Allégaten 41, 5007, Bergen, Norway.

出版信息

ChemMedChem. 2021 Sep 6;16(17):2715-2726. doi: 10.1002/cmdc.202100302. Epub 2021 Aug 6.

DOI:10.1002/cmdc.202100302
PMID:34189850
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8518799/
Abstract

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.

摘要

FabF（3-氧代酰基-[酰基载体蛋白]合酶 2），它催化脂肪酸合成 II 途径中的限速缩合反应，是新型抗生素的一个有吸引力的靶标。在这里，我们重点研究铜绿假单胞菌的 FabF（PaFabF），因为迫切需要针对这种病原体的抗生素。为了便于探索这一目标，我们建立了一个实验工具箱，包括使用生物层干涉法（BLI）以及饱和转移差异（STD）和 WaterLOGSY NMR 进行的结合测定，以及用于结构测定的稳健条件。通过验证从虚拟筛选中获得的命中物，证明了该工具箱支持 FabF 抑制剂的基于结构的设计的适用性。对近 500 万种化合物文库的筛选产生了 6 种化合物，这些化合物显示与 FabF 的丙二酰基结合位点结合。其中一个命中物的复合物与 PaFabF 的晶体结构被确定。基于获得的结合模式，设计并合成了类似物，但亲和力无法提高。这项工作为基于结构的 PaFabF 探索奠定了基础。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a834/8518799/f8d72f7814d2/CMDC-16-2715-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a834/8518799/c48aec4acda7/CMDC-16-2715-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a834/8518799/b02fd385bbee/CMDC-16-2715-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a834/8518799/86d564de4cdc/CMDC-16-2715-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a834/8518799/8b00bc357f2a/CMDC-16-2715-g018.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a834/8518799/d9725ce64945/CMDC-16-2715-g017.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a834/8518799/106f430d75ff/CMDC-16-2715-g023.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a834/8518799/9c010a9b7007/CMDC-16-2715-g024.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a834/8518799/fbf853761a6e/CMDC-16-2715-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a834/8518799/164a0c19d438/CMDC-16-2715-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a834/8518799/f8d72f7814d2/CMDC-16-2715-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a834/8518799/c48aec4acda7/CMDC-16-2715-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a834/8518799/b02fd385bbee/CMDC-16-2715-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a834/8518799/86d564de4cdc/CMDC-16-2715-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a834/8518799/8b00bc357f2a/CMDC-16-2715-g018.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a834/8518799/d9725ce64945/CMDC-16-2715-g017.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a834/8518799/106f430d75ff/CMDC-16-2715-g023.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a834/8518799/9c010a9b7007/CMDC-16-2715-g024.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a834/8518799/fbf853761a6e/CMDC-16-2715-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a834/8518799/164a0c19d438/CMDC-16-2715-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a834/8518799/f8d72f7814d2/CMDC-16-2715-g008.jpg

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