Hit optimization by dynamic combinatorial chemistry on energy-coupling factor transporter ECF-PanT.
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
Author Information
Ioulia Antonia Exapicheidou: Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), 66123, Saarbrücken, Germany. anna.hirsch@helmholtz-hips.de. ORCID
Atanaz Shams: Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), 66123, Saarbrücken, Germany. anna.hirsch@helmholtz-hips.de. ORCID
Hamza Ibrahim: Data Driven Drug Design Group, Center for Bioinformatics, Saarland Informatics Campus E2.1, Saarland University, Saarbrücken 66123, Germany.
Aleksei Tsarenko: Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 4, 9747, AG, Groningen, The Netherlands.
Michael Backenköhler: Data Driven Drug Design Group, Center for Bioinformatics, Saarland Informatics Campus E2.1, Saarland University, Saarbrücken 66123, Germany.
Mostafa M Hamed: Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), 66123, Saarbrücken, Germany. anna.hirsch@helmholtz-hips.de. ORCID
Eleonora Diamanti: Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), 66123, Saarbrücken, Germany. anna.hirsch@helmholtz-hips.de.
Andrea Volkamer: Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), 66123, Saarbrücken, Germany. anna.hirsch@helmholtz-hips.de. ORCID
Dirk J Slotboom: Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 4, 9747, AG, Groningen, The Netherlands.
Anna K H Hirsch: Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), 66123, Saarbrücken, Germany. anna.hirsch@helmholtz-hips.de. ORCID
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 . 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.
