Hit optimization by dynamic combinatorial chemistry on Streptococcus pneumoniae 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 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.

Citation

Ioulia Antonia Exapicheidou, Atanaz Shams, Hamza Ibrahim, Aleksei Tsarenko, Michael Backenköhler, Mostafa M Hamed, Eleonora Diamanti, Andrea Volkamer, Dirk J Slotboom, Anna K H Hirsch. Hit optimization by dynamic combinatorial chemistry on Streptococcus pneumoniae energy-coupling factor transporter ECF-PanT. Chemical communications (Cambridge, England). 2024 Jan 18;60(7):870-873

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PMID: 38164786

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