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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: Pöhner, Ina (VerfasserIn) , Quotadamo, Antonio (VerfasserIn) , Panecka-Hofman, Joanna (VerfasserIn) , Luciani, Rosaria (VerfasserIn) , Santucci, Matteo (VerfasserIn) , Linciano, Pasquale (VerfasserIn) , Landi, Giacomo (VerfasserIn) , Di Pisa, Flavio (VerfasserIn) , Dello Iacono, Lucia (VerfasserIn) , Pozzi, Cecilia (VerfasserIn) , Mangani, Stefano (VerfasserIn) , Gul, Sheraz (VerfasserIn) , Witt, Gesa (VerfasserIn) , Ellinger, Bernhard (VerfasserIn) , Kuzikov, Maria (VerfasserIn) , Santarem, Nuno (VerfasserIn) , Cordeiro-da-Silva, Anabela (VerfasserIn) , Costi, Maria P. (VerfasserIn) , Venturelli, Alberto (VerfasserIn) , Wade, Rebecca C. (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: June 8, 2022
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
Volltext
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
Beschreibung
Zusammenfassung: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.
Beschreibung:Gesehen am 15.09.2022
Beschreibung:Online Resource
ISSN:1520-4804
DOI:10.1021/acs.jmedchem.2c00232

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