Hit optimization by dynamic combinatorial chemistry on Streptococcus pneumoniae energy-coupling factor transporter
Ioulia Antonia Exapicheidou1,2, Atanaz Shams1,2, Hamza Ibrahim3
1Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), 66123, Saarbrücken, Germany. anna.hirsch@helmholtz-hips.de.
Abstract:
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.
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