Issue 7, 2024

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

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.

Graphical abstract: Hit optimization by dynamic combinatorial chemistry on Streptococcus pneumoniae energy-coupling factor transporter ECF-PanT

Supplementary files

Article information

Article type
Communication
Submitted
23 sen 2023
Accepted
11 dek 2023
First published
02 yan 2024

Chem. Commun., 2024,60, 870-873

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

I. A. Exapicheidou, A. Shams, H. Ibrahim, A. Tsarenko, M. Backenköhler, M. M. Hamed, E. Diamanti, A. Volkamer, D. J. Slotboom and A. K. H. Hirsch, Chem. Commun., 2024, 60, 870 DOI: 10.1039/D3CC04738E

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