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.
Highlights
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 revealed that most potent quorum sensing inhibitor (QSI) of this class act as inverse agonists rather than antagonists on the target receptor.[24]
We were able to solve a co-crystal structure of 11 in complex with the ligand binding domain of Pseudomonas quinolone signal (PQS) receptor (PqsR) (Figure 3a), clearly showing that the linker establishes an angled connection between the 2-amino-pyridine headgroup, which occupies the space of the quinolone core of the natural ligands while the 4fluorophenyl ring which points into the alkyl-chain pocket
Summary
Michael Zender,[a] Florian Witzgall,[c] Alexander Kiefer,[a] Benjamin Kirsch,[a]. Christine K. 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. 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). Hit optimization involved growth vector identification and exploitation. 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
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