6Q7W

Crystal structure of PqsR (MvfR) ligand-binding domain in complex with compound 20

Summary for 6Q7W

• Entry DOI: 10.2210/pdb6q7w/pdb
• Descriptor: Transcriptional regulator MvfR, ~{N}4-[3-(4-fluorophenyl)propyl]-6-(trifluoromethyl)pyridine-2,4-diamine, GLYCEROL, ... (4 entities in total)
• Functional Keywords: quorum sensing, lysr-type transcriptional regulator, pseudomonas quinolone signaling system, lttr, dna binding protein
• Biological source: Pseudomonas aeruginosa PAO1
• Total number of polymer chains: 1
• Total formula weight: 26197.55

Authors

Witzgall, F.,Blankenfeldt, W. (deposition date: 2018-12-13, release date: 2019-11-20, Last modification date: 2024-01-24)

Primary citation

Zender, M.,Witzgall, F.,Kiefer, A.,Kirsch, B.,Maurer, C.K.,Kany, A.M.,Xu, N.,Schmelz, S.,Borger, C.,Blankenfeldt, W.,Empting, M.
Flexible Fragment Growing Boosts Potency of Quorum-Sensing Inhibitors against Pseudomonas aeruginosa Virulence.
Chemmedchem, 15:188-194, 2020

PubMed Abstract: Hit-to-lead optimization is a critical phase in drug discovery. Herein, we report on the fragment-based discovery and optimization of 2-aminopyridine derivatives as a novel lead-like structure for the treatment of the dangerous opportunistic pathogen Pseudomonas aeruginosa. We pursue an innovative treatment strategy by interfering with the Pseudomonas quinolone signal (PQS) quorum sensing (QS) system leading to an abolishment of bacterial pathogenicity. Our compounds act on the PQS receptor (PqsR), a key transcription factor controlling the expression of various pathogenicity determinants. In this target-driven approach, we made use of biophysical screening via surface plasmon resonance (SPR) followed by isothermal titration calorimetry (ITC)-enabled enthalpic efficiency (EE) evaluation. Hit optimization then involved growth vector identification and exploitation. Astonishingly, the latter was successfully achieved by introducing flexible linkers rather than rigid motifs leading to a boost in activity on the target receptor and anti-virulence potency.

PubMed: 31709767
DOI: 10.1002/cmdc.201900621

Experimental method

X-RAY DIFFRACTION (2.82 Å)