Hit optimization by dynamic combinatorial chemistry on energy-coupling factor transporter ECF-PanT

Herein, we present the first application of target-directed dynamic combinatorial chemistry (tdDCC) to the whole complex of the highly dynamic transmembrane, energy-coupling factor (ECF) transporter ECF-PanT in Streptococcus pneumoniae . In addition, we successfully employed the tdDCC technique as a...

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Published in:Chemical communications (Cambridge, England) England), 2024-01, Vol.6 (7), p.87-873
Main Authors: Exapicheidou, Ioulia Antonia, Shams, Atanaz, Ibrahim, Hamza, Tsarenko, Aleksei, Backenköhler, Michael, Hamed, Mostafa M, Diamanti, Eleonora, Volkamer, Andrea, Slotboom, Dirk J, Hirsch, Anna K. H
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Summary:Herein, we present the first application of target-directed dynamic combinatorial chemistry (tdDCC) to the whole complex of the highly dynamic transmembrane, energy-coupling factor (ECF) transporter ECF-PanT in Streptococcus pneumoniae . In addition, we successfully employed the tdDCC technique as a hit-identification and -optimization strategy that led to the identification of optimized ECF inhibitors with improved activity. We characterized the best compounds regarding cytotoxicity and performed computational modeling studies on the crystal structure of ECF-PanT to rationalize their binding mode. Notably, docking studies showed that the acylhydrazone linker is able to maintain the crucial interactions. First application of dynamic combinatorial chemistry to the whole complex of the energy-coupling factor transporter PanT from Streptococcus pneumoniae .
ISSN:1359-7345
1364-548X
DOI:10.1039/d3cc04738e