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Nowacki, M.* ; Cardoso Micu Menezes, F.M. ; Pykacz, E. ; Popiołek, M.* ; Napolitano, V. ; Krishna, C.K.* ; Kalel, V.C.* ; Erdmann, R.* ; Fröhlich, T. ; Plettenburg, O. ; Sattler, M. ; Popowicz, G.M. ; Dawidowski, M.*

Quantum mechanics-driven structure-activity relationship study of PEX5-PEX14 protein-protein interaction inhibitors based on a dibenzo[b,e]azepin-6(6H)-one scaffold.

Eur. J. Med. Chem. 298:117979 (2025)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
Targeting protein-protein interactions (PPIs) is a promising strategy in drug development. However, despite the considerable progress in the field, targeting PPIs with small molecules remains challenging, requiring novel strategies in inhibitor design and subsequent structure-activity relationship (SAR) studies. We have recently identified the PEX5-PEX14 PPI as a novel therapeutic target against diseases related to Trypanosoma infections and discovered small-molecule inhibitors against PEX14 using structure-based drug discovery (SBDD). The current study demonstrates that combining SBDD with quantum mechanical (QM) energy decomposition and deconvolution analysis (EDDA) provides an in-depth understanding of SAR in the newly developed PPI inhibitors class. We obtained diverse dibenzo[b,e]azepin-6(6H)-one PEX14 inhibitors, which resulted from redesigning the central scaffold of one of the previous compound lines and follow-up modifications. The diversification strategy yielded compounds obtained by multicomponent reactions (MCRs), from which the Kabachnik-Fields reaction products were the most potent tricyclic PEX5-PEX14 PPI inhibitors obtained so far. Overall, the activities of the compounds measured with biophysical assays aligned with the QM-derived compound binding energies. Hence, using an advanced computational approach, our results pave an alternative way for SAR rationalization of compounds against PPI targets.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Dibenzo[b,e]azepin-6(6h)-one ; Multicomponent Reactions ; Protein-protein Interaction Inhibitors ; Quantum Mechanical Energy Decomposition And Deconvolution Analysis ; Structure-activity Relationship ; Structure-based Drug Design ; Trypanocidal Inhibitors; Small-molecule Inhibitors; Discovery; Design; Pex14; Efficient; Import; Model; Drug
ISSN (print) / ISBN 0223-5234
e-ISSN 1768-3254
Zeitschrift European Journal of Medicinal Chemistry
Quellenangaben Band: 298, Heft: , Seiten: , Artikelnummer: 117979 Supplement: ,
Verlag Elsevier
Verlagsort Amsterdam [u.a.]
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Structural Biology (STB)
Institute of Medicinal Chemistry (IMC)
Förderungen Bundesministerium fur Bildung und Forschung
Bundesministerium fr Wirtschaft und Klimaschutz
Deutsche Forschungsgemeinschaft
Ruhr University Bochum, InnovationsFoRUM
Narodowe Centrum Nauki