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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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Main Authors: Pöhner, Ina (Author) , Quotadamo, Antonio (Author) , Panecka-Hofman, Joanna (Author) , Luciani, Rosaria (Author) , Santucci, Matteo (Author) , Linciano, Pasquale (Author) , Landi, Giacomo (Author) , Di Pisa, Flavio (Author) , Dello Iacono, Lucia (Author) , Pozzi, Cecilia (Author) , Mangani, Stefano (Author) , Gul, Sheraz (Author) , Witt, Gesa (Author) , Ellinger, Bernhard (Author) , Kuzikov, Maria (Author) , Santarem, Nuno (Author) , Cordeiro-da-Silva, Anabela (Author) , Costi, Maria P. (Author) , Venturelli, Alberto (Author) , Wade, Rebecca C. (Author)
Format: Article (Journal)
Language:English
Published: June 8, 2022
In: Journal of medicinal chemistry
Year: 2022, Volume: 65, Issue: 13, Pages: 9011-9033
ISSN:1520-4804
DOI:10.1021/acs.jmedchem.2c00232
Online Access: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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Author Notes: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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Summary: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.
Item Description:Gesehen am 15.09.2022
Physical Description:Online Resource
ISSN:1520-4804
DOI:10.1021/acs.jmedchem.2c00232

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