Investigation of the Compatibility between Warheads and Peptidomimetic Sequences of Protease Inhibitors—A Comprehensive Reactivity and Selectivity Study
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 pro...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/8/7226 |
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| author | Patrick Müller Mergim Meta Jan Laurenz Meidner Marvin Schwickert Jessica Meyr Kevin Schwickert Christian Kersten Collin Zimmer Stefan Josef Hammerschmidt Ariane Frey Albin Lahu Sergio de la Hoz-Rodríguez Laura Agost-Beltrán Santiago Rodríguez Kira Diemer Wilhelm Neumann Florenci V. Gonzàlez Bernd Engels Tanja Schirmeister |
| author_facet | Patrick Müller Mergim Meta Jan Laurenz Meidner Marvin Schwickert Jessica Meyr Kevin Schwickert Christian Kersten Collin Zimmer Stefan Josef Hammerschmidt Ariane Frey Albin Lahu Sergio de la Hoz-Rodríguez Laura Agost-Beltrán Santiago Rodríguez Kira Diemer Wilhelm Neumann Florenci V. Gonzàlez Bernd Engels Tanja Schirmeister |
| author_sort | Patrick Müller |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T04:56:41Z |
| format | Article |
| id | doaj.art-ff4da91785ec460c9d3be381dd2c4081 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T04:56:41Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-ff4da91785ec460c9d3be381dd2c40812023-11-17T19:37:11ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-04-01248722610.3390/ijms24087226Investigation of the Compatibility between Warheads and Peptidomimetic Sequences of Protease Inhibitors—A Comprehensive Reactivity and Selectivity StudyPatrick Müller0Mergim Meta1Jan Laurenz Meidner2Marvin Schwickert3Jessica Meyr4Kevin Schwickert5Christian Kersten6Collin Zimmer7Stefan Josef Hammerschmidt8Ariane Frey9Albin Lahu10Sergio de la Hoz-Rodríguez11Laura Agost-Beltrán12Santiago Rodríguez13Kira Diemer14Wilhelm Neumann15Florenci V. Gonzàlez16Bernd Engels17Tanja Schirmeister18Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudinger Weg 5, D-55128 Mainz, GermanyInstitute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudinger Weg 5, D-55128 Mainz, GermanyInstitute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudinger Weg 5, D-55128 Mainz, GermanyInstitute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudinger Weg 5, D-55128 Mainz, GermanyInstitute of Physical and Theoretical Chemistry, Julius-Maximilians-University of Wuerzburg, Emil-Fischer-Straße 42 Süd, D-97074 Wuerzburg, GermanyInstitute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudinger Weg 5, D-55128 Mainz, GermanyInstitute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudinger Weg 5, D-55128 Mainz, GermanyInstitute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudinger Weg 5, D-55128 Mainz, GermanyInstitute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudinger Weg 5, D-55128 Mainz, GermanyInstitute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudinger Weg 5, D-55128 Mainz, GermanyInstitute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudinger Weg 5, D-55128 Mainz, GermanyDepartament de Química Inorgànica i Orgànica, Universitat Jaume I, 12080 Castelló de la Pana, SpainDepartament de Química Inorgànica i Orgànica, Universitat Jaume I, 12080 Castelló de la Pana, SpainDepartament de Química Inorgànica i Orgànica, Universitat Jaume I, 12080 Castelló de la Pana, SpainInstitute of Physical and Theoretical Chemistry, Julius-Maximilians-University of Wuerzburg, Emil-Fischer-Straße 42 Süd, D-97074 Wuerzburg, GermanyInstitute of Physical and Theoretical Chemistry, Julius-Maximilians-University of Wuerzburg, Emil-Fischer-Straße 42 Süd, D-97074 Wuerzburg, GermanyDepartament de Química Inorgànica i Orgànica, Universitat Jaume I, 12080 Castelló de la Pana, SpainInstitute of Physical and Theoretical Chemistry, Julius-Maximilians-University of Wuerzburg, Emil-Fischer-Straße 42 Süd, D-97074 Wuerzburg, GermanyInstitute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudinger Weg 5, D-55128 Mainz, GermanyCovalent 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.https://www.mdpi.com/1422-0067/24/8/7226covalent inhibitorsin vitro studyprotease inhibitorspeptidomimetic sequencewarheadreactivity and selectivity study |
| spellingShingle | Patrick Müller Mergim Meta Jan Laurenz Meidner Marvin Schwickert Jessica Meyr Kevin Schwickert Christian Kersten Collin Zimmer Stefan Josef Hammerschmidt Ariane Frey Albin Lahu Sergio de la Hoz-Rodríguez Laura Agost-Beltrán Santiago Rodríguez Kira Diemer Wilhelm Neumann Florenci V. Gonzàlez Bernd Engels Tanja Schirmeister Investigation of the Compatibility between Warheads and Peptidomimetic Sequences of Protease Inhibitors—A Comprehensive Reactivity and Selectivity Study International Journal of Molecular Sciences covalent inhibitors in vitro study protease inhibitors peptidomimetic sequence warhead reactivity and selectivity study |
| title | Investigation of the Compatibility between Warheads and Peptidomimetic Sequences of Protease Inhibitors—A Comprehensive Reactivity and Selectivity Study |
| title_full | Investigation of the Compatibility between Warheads and Peptidomimetic Sequences of Protease Inhibitors—A Comprehensive Reactivity and Selectivity Study |
| title_fullStr | Investigation of the Compatibility between Warheads and Peptidomimetic Sequences of Protease Inhibitors—A Comprehensive Reactivity and Selectivity Study |
| title_full_unstemmed | Investigation of the Compatibility between Warheads and Peptidomimetic Sequences of Protease Inhibitors—A Comprehensive Reactivity and Selectivity Study |
| title_short | Investigation of the Compatibility between Warheads and Peptidomimetic Sequences of Protease Inhibitors—A Comprehensive Reactivity and Selectivity Study |
| title_sort | investigation of the compatibility between warheads and peptidomimetic sequences of protease inhibitors a comprehensive reactivity and selectivity study |
| topic | covalent inhibitors in vitro study protease inhibitors peptidomimetic sequence warhead reactivity and selectivity study |
| url | https://www.mdpi.com/1422-0067/24/8/7226 |
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