Investigation of the Compatibility between Warheads and Peptidomimetic Sequences of Protease Inhibitors—A Comprehensive Reactivity and Selectivity Study
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Otros documentos de la autoría: Müller, Patrick; Meta, Mergim; Meidner, Jan Laurenz; Schwickert, Marvin; Meyr, Jessica; Schwickert, Dr. Kevin; Kersten, Christian; Zimmer, Collin; Hammerschmidt, Stefan Josef; Frey, Ariane; Lahu, Albin; de la hoz rodriguez, Sergio; Agost Beltrán, Laura; Rodríguez, Santiago; Diemer, Kira; Neumann, Wilhelm; González, Florenci; Engels, Bernd; Schirmeister, Tanja
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Título
Investigation of the Compatibility between Warheads and Peptidomimetic Sequences of Protease Inhibitors—A Comprehensive Reactivity and Selectivity StudyAutoría
Fecha de publicación
2023-04-13Editor
MDPIISSN
1661-6596; 1422-0067Cita bibliográfica
Müller, Patrick, Mergim Meta, Jan Laurenz Meidner, Marvin Schwickert, Jessica Meyr, Kevin Schwickert, Christian Kersten, Collin Zimmer, Stefan Josef Hammerschmidt, Ariane Frey, and et al. 2023. "Investigation of the Compatibility between Warheads and Peptidomimetic Sequences of Protease Inhibitors—A Comprehensive Reactivity and Selectivity Study" International Journal of Molecular Sciences 24, no. 8: 7226. https://doi.org/10.3390/ijms24087226Tipo de documento
info:eu-repo/semantics/articleVersión
info:eu-repo/semantics/publishedVersionPalabras clave / Materias
Resumen
: Covalent peptidomimetic protease inhibitors have gained a lot of attention in drug development in recent years. They are designed to covalently bind the catalytically active amino acids
through electrophilic groups ... [+]
: Covalent peptidomimetic protease inhibitors have gained a lot of attention in drug development in recent years. They are designed to covalently bind the catalytically active amino acids
through electrophilic groups called warheads. Covalent inhibition has an advantage in terms of
pharmacodynamic properties but can also bear toxicity risks due to non-selective off-target protein
binding. Therefore, the right combination of a reactive warhead with a well-suited peptidomimetic
sequence is of great importance. Herein, the selectivities of well-known warheads combined with
peptidomimetic sequences suited for five different proteases were investigated, highlighting the
impact of both structure parts (warhead and peptidomimetic sequence) for affinity and selectivity.
Molecular docking gave insights into the predicted binding modes of the inhibitors inside the binding
pockets of the different enzymes. Moreover, the warheads were investigated by NMR and LC-MS
reactivity assays against serine/threonine and cysteine nucleophile models, as well as by quantum
mechanics simulations. [-]
Publicado en
Int. J. Mol. Sci. 2023, 24, 7226. https://doi.org/10.3390/ijms24087226Entidad financiadora
Deutsche Forschungsgemeinschaft (DFG) | Generalitat Valenciana | Universitat Jaume I | Ministerio de Ciencia, Innovación y Universidades
Código del proyecto o subvención
project Q5 | CIPROM/2021/079 | UJI-B2021-71 | FPU19/04913
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