Details
| Originalsprache | Englisch |
|---|---|
| Aufsatznummer | 117979 |
| Fachzeitschrift | European Journal of Medicinal Chemistry |
| Jahrgang | 298 |
| Frühes Online-Datum | 18 Juli 2025 |
| Publikationsstatus | Veröffentlicht - 15 Nov. 2025 |
Abstract
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.
ASJC Scopus Sachgebiete
- Pharmakologie, Toxikologie und Pharmazie (insg.)
- Pharmakologie
- Pharmakologie, Toxikologie und Pharmazie (insg.)
- Wirkstoffforschung
- Chemie (insg.)
- Organische Chemie
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in: European Journal of Medicinal Chemistry, Jahrgang 298, 117979, 15.11.2025.
Publikation: Beitrag in Fachzeitschrift › Artikel › Forschung › Peer-Review
}
TY - JOUR
T1 - 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
AU - Nowacki, Michał
AU - Menezes, Filipe
AU - Pykacz, Emilia
AU - Popiołek, Mateusz
AU - Napolitano, Valeria
AU - Krishna, Chethan K.
AU - Kalel, Vishal C.
AU - Erdmann, Ralf
AU - Fröhlich, Tony
AU - Plettenburg, Oliver
AU - Sattler, Michael
AU - Popowicz, Grzegorz M.
AU - Dawidowski, Maciej
N1 - Publisher Copyright: © 2025 The Authors
PY - 2025/11/15
Y1 - 2025/11/15
N2 - 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.
AB - 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.
KW - Dibenzo[b,e]azepin-6(6H)-one
KW - Multicomponent reactions
KW - Protein-protein interaction inhibitors
KW - Quantum mechanical energy decomposition and deconvolution analysis
KW - Structure-activity relationship
KW - Structure-based drug design
KW - Trypanocidal inhibitors
UR - http://www.scopus.com/inward/record.url?scp=105012091213&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2025.117979
DO - 10.1016/j.ejmech.2025.117979
M3 - Article
AN - SCOPUS:105012091213
VL - 298
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
M1 - 117979
ER -