Multitarget, selective compound design yields potent inhibitors of a kinetoplastid pteridine reductase 1
The optimization of compounds with multiple targets is a difficult multidimensional problem in the drug discovery cycle. Here, we present a systematic, multidisciplinary approach to the development of selective antiparasitic compounds. Computational fragment-based design of novel pteridine derivatives...
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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
June 8, 2022
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| In: |
Journal of medicinal chemistry
Year: 2022, Jahrgang: 65, Heft: 13, Pages: 9011-9033 |
| ISSN: | 1520-4804 |
| DOI: | 10.1021/acs.jmedchem.2c00232 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1021/acs.jmedchem.2c00232 Verlag, lizenzpflichtig, Volltext: https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c00232 
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| Verfasserangaben: | Ina Pöhner, Antonio Quotadamo, Joanna Panecka-Hofman, Rosaria Luciani, Matteo Santucci, Pasquale Linciano, Giacomo Landi, Flavio Di Pisa, Lucia Dello Iacono, Cecilia Pozzi, Stefano Mangani, Sheraz Gul, Gesa Witt, Bernhard Ellinger, Maria Kuzikov, Nuno Santarem, Anabela Cordeiro-da-Silva, Maria P. Costi, Alberto Venturelli, and Rebecca C. Wade |
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| 245 | 1 | 0 | |a Multitarget, selective compound design yields potent inhibitors of a kinetoplastid pteridine reductase 1 |c Ina Pöhner, Antonio Quotadamo, Joanna Panecka-Hofman, Rosaria Luciani, Matteo Santucci, Pasquale Linciano, Giacomo Landi, Flavio Di Pisa, Lucia Dello Iacono, Cecilia Pozzi, Stefano Mangani, Sheraz Gul, Gesa Witt, Bernhard Ellinger, Maria Kuzikov, Nuno Santarem, Anabela Cordeiro-da-Silva, Maria P. Costi, Alberto Venturelli, and Rebecca C. Wade |
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| 520 | |a The optimization of compounds with multiple targets is a difficult multidimensional problem in the drug discovery cycle. Here, we present a systematic, multidisciplinary approach to the development of selective antiparasitic compounds. Computational fragment-based design of novel pteridine derivatives along with iterations of crystallographic structure determination allowed for the derivation of a structure−activity relationship for multitarget inhibition. The approach yielded compounds showing apparent picomolar inhibition of T. brucei pteridine reductase 1 (PTR1), nanomolar inhibition of L. major PTR1, and selective submicromolar inhibition of parasite dihydrofolate reductase (DHFR) versus human DHFR. Moreover, by combining design for polypharmacology with a property-based on-parasite optimization, we found three compounds that exhibited micromolar EC50 values against T. brucei brucei while retaining their target inhibition. Our results provide a basis for the further development of pteridine-based compounds, and we expect our multitarget approach to be generally applicable to the design and optimization of anti-infective agents. | ||
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