6q7u
From Proteopedia
Crystal structure of PqsR (MvfR) ligand-binding domain in complex with HHQ
Structural highlights
Function[MVFR_PSEAE] Transcription regulator that plays a critical role in virulence by positively regulating the expression of multiple quorum sensing (QS)-regulated virulence factors, genes involved in protein secretion, translation, response to oxidative stress and the phnAB operon (PubMed:11724939, PubMed:27678057, PubMed:17083468). At the stationary phase, negatively autoregulates its function through cleavage and translocation to the extracellular space (PubMed:11724939).[1] [2] [3] Publication Abstract from PubMedHit-to-lead optimization is a critical phase in drug discovery. Herein, we report on the fragment-based discovery and optimization of 2-amino pyridine 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. Flexible Fragment Growing Boosts Potency of Quorum Sensing Inhibitors against Pseudomonas aeruginosa Virulence.,Zender M, Witzgall F, Kiefer AF, Kirsch B, Maurer CK, Kany AM, Xu N, Schmelz S, Borger C, Blankenfeldt W, Empting M ChemMedChem. 2019 Nov 11. doi: 10.1002/cmdc.201900621. PMID:31709767[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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