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An Experimental Toolbox for Structure‐Based Hit Discovery for P . aeruginosa FabF, a Promising Target for Antibiotics
Author(s) -
Espeland Ludvik Olai,
Georgiou Charis,
Klein Raphael,
Bhukya Hemalatha,
Haug Bengt Erik,
Underhaug Jarl,
Mainkar Prathama S.,
Brenk Ruth
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202100302
Subject(s) - toolbox , computational biology , virtual screening , antibiotics , limiting , chemistry , drug discovery , combinatorial chemistry , biochemistry , stereochemistry , biology , computer science , mechanical engineering , engineering , programming language
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 ( Pa FabF) 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 Pa FabF 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 Pa FabF.