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https://doi.org/10.21256/zhaw-1683| Publikationstyp: | Beitrag in wissenschaftlicher Zeitschrift |
| Art der Begutachtung: | Peer review (Publikation) |
| Titel: | Molecular recognition of the catalytic zinc(II) ion in MMP-13 : structure-based evolution of an allosteric inhibitor to dual binding mode inhibitors with improved lipophilic ligand efficiencies |
| Autor/-in: | Fischer, Thomas Riedl, Rainer |
| DOI: | 10.3390/ijms17030314 10.21256/zhaw-1683 |
| Erschienen in: | International Journal of Molecular Sciences |
| Band(Heft): | 17 |
| Heft: | 3/314 |
| Erscheinungsdatum: | 2016 |
| Verlag / Hrsg. Institution: | MDPI |
| ISSN: | 1422-0067 1661-6596 |
| Sprache: | Englisch |
| Schlagwörter: | Structure-based drug design; Medicinal chemistry; Organic chemistry |
| Fachgebiet (DDC): | 572: Biochemie 615: Pharmakologie und Therapeutik |
| Zusammenfassung: | Matrix metalloproteinases (MMPs) are a class of zinc dependent endopeptidases which play a crucial role in a multitude of severe diseases such as cancer and osteoarthritis. We employed MMP-13 as the target enzyme for the structure-based design and synthesis of inhibitors able to recognize the catalytic zinc ion in addition to an allosteric binding site in order to increase the affinity of the ligand. Guided by molecular modeling, we optimized an initial allosteric inhibitor by addition of linker fragments and weak zinc binders for recognition of the catalytic center. Furthermore we improved the lipophilic ligand efficiency (LLE) of the initial inhibitor by adding appropriate zinc binding fragments to lower the clogP values of the inhibitors, while maintaining their potency. All synthesized inhibitors showed elevated affinity compared to the initial hit, also most of the novel inhibitors displayed better LLE. Derivatives with carboxylic acids as the zinc binding fragments turned out to be the most potent inhibitors (compound 3 (ZHAWOC5077): IC50 = 134 nM) whereas acyl sulfonamides showed the best lipophilic ligand efficiencies (compound 18 (ZHAWOC5135): LLE = 2.91). |
| URI: | https://digitalcollection.zhaw.ch/handle/11475/2838 |
| Volltext Version: | Publizierte Version |
| Lizenz (gemäss Verlagsvertrag): | CC BY 4.0: Namensnennung 4.0 International |
| Departement: | Life Sciences und Facility Management |
| Enthalten in den Sammlungen: | Publikationen Life Sciences und Facility Management |
Dateien zu dieser Ressource:
| Datei | Beschreibung | Größe | Format | |
|---|---|---|---|---|
| 2016_Fischer_Molecular recognition_International Journal of Molecular Sciences.pdf | 3.31 MB | Adobe PDF |  Öffnen/Anzeigen |
Zur Langanzeige
Fischer, T., & Riedl, R. (2016). Molecular recognition of the catalytic zinc(II) ion in MMP-13 : structure-based evolution of an allosteric inhibitor to dual binding mode inhibitors with improved lipophilic ligand efficiencies. International Journal of Molecular Sciences, 17(3/314). https://doi.org/10.3390/ijms17030314
Fischer, T. and Riedl, R. (2016) ‘Molecular recognition of the catalytic zinc(II) ion in MMP-13 : structure-based evolution of an allosteric inhibitor to dual binding mode inhibitors with improved lipophilic ligand efficiencies’, International Journal of Molecular Sciences, 17(3/314). Available at: https://doi.org/10.3390/ijms17030314.
T. Fischer and R. Riedl, “Molecular recognition of the catalytic zinc(II) ion in MMP-13 : structure-based evolution of an allosteric inhibitor to dual binding mode inhibitors with improved lipophilic ligand efficiencies,” International Journal of Molecular Sciences, vol. 17, no. 3/314, 2016, doi: 10.3390/ijms17030314.
FISCHER, Thomas und Rainer RIEDL, 2016. Molecular recognition of the catalytic zinc(II) ion in MMP-13 : structure-based evolution of an allosteric inhibitor to dual binding mode inhibitors with improved lipophilic ligand efficiencies. International Journal of Molecular Sciences. 2016. Bd. 17, Nr. 3/314. DOI 10.3390/ijms17030314
Fischer, Thomas, and Rainer Riedl. 2016. “Molecular Recognition of the Catalytic zinc(II) Ion in MMP-13 : Structure-Based Evolution of an Allosteric Inhibitor to Dual Binding Mode Inhibitors with Improved Lipophilic Ligand Efficiencies.” International Journal of Molecular Sciences 17 (3/314). https://doi.org/10.3390/ijms17030314.
Fischer, Thomas, and Rainer Riedl. “Molecular Recognition of the Catalytic zinc(II) Ion in MMP-13 : Structure-Based Evolution of an Allosteric Inhibitor to Dual Binding Mode Inhibitors with Improved Lipophilic Ligand Efficiencies.” International Journal of Molecular Sciences, vol. 17, no. 3/314, 2016, https://doi.org/10.3390/ijms17030314.
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