Investigation of the Compatibility between Warheads and Peptidomimetic Sequences of Protease Inhibitors-A Comprehensive Reactivity and Selectivity Study.

Autor: Müller P; Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudinger Weg 5, D-55128 Mainz, Germany., Meta M; Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudinger Weg 5, D-55128 Mainz, Germany., Meidner JL; Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudinger Weg 5, D-55128 Mainz, Germany., Schwickert M; Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudinger Weg 5, D-55128 Mainz, Germany., Meyr J; Institute of Physical and Theoretical Chemistry, Julius-Maximilians-University of Wuerzburg, Emil-Fischer-Straße 42 Süd, D-97074 Wuerzburg, Germany., Schwickert K; Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudinger Weg 5, D-55128 Mainz, Germany., Kersten C; Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudinger Weg 5, D-55128 Mainz, Germany., Zimmer C; Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudinger Weg 5, D-55128 Mainz, Germany., Hammerschmidt SJ; Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudinger Weg 5, D-55128 Mainz, Germany., Frey A; Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudinger Weg 5, D-55128 Mainz, Germany., Lahu A; Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudinger Weg 5, D-55128 Mainz, Germany., de la Hoz-Rodríguez S; Departament de Química Inorgànica i Orgànica, Universitat Jaume I, 12080 Castelló de la Pana, Spain., Agost-Beltrán L; Departament de Química Inorgànica i Orgànica, Universitat Jaume I, 12080 Castelló de la Pana, Spain., Rodríguez S; Departament de Química Inorgànica i Orgànica, Universitat Jaume I, 12080 Castelló de la Pana, Spain., Diemer K; Institute of Physical and Theoretical Chemistry, Julius-Maximilians-University of Wuerzburg, Emil-Fischer-Straße 42 Süd, D-97074 Wuerzburg, Germany., Neumann W; Institute of Physical and Theoretical Chemistry, Julius-Maximilians-University of Wuerzburg, Emil-Fischer-Straße 42 Süd, D-97074 Wuerzburg, Germany., Gonzàlez FV; Departament de Química Inorgànica i Orgànica, Universitat Jaume I, 12080 Castelló de la Pana, Spain., Engels B; Institute of Physical and Theoretical Chemistry, Julius-Maximilians-University of Wuerzburg, Emil-Fischer-Straße 42 Süd, D-97074 Wuerzburg, Germany., Schirmeister T; Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudinger Weg 5, D-55128 Mainz, Germany.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2023 Apr 13; Vol. 24 (8). Date of Electronic Publication: 2023 Apr 13.
DOI: 10.3390/ijms24087226
Abstrakt: 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.
Databáze: MEDLINE
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