Copertina

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...

Descrizione completa

Salvato in:
Dettagli Bibliografici
Autori principali: Pöhner, Ina (Autore) , Quotadamo, Antonio (Autore) , Panecka-Hofman, Joanna (Autore) , Luciani, Rosaria (Autore) , Santucci, Matteo (Autore) , Linciano, Pasquale (Autore) , Landi, Giacomo (Autore) , Di Pisa, Flavio (Autore) , Dello Iacono, Lucia (Autore) , Pozzi, Cecilia (Autore) , Mangani, Stefano (Autore) , Gul, Sheraz (Autore) , Witt, Gesa (Autore) , Ellinger, Bernhard (Autore) , Kuzikov, Maria (Autore) , Santarem, Nuno (Autore) , Cordeiro-da-Silva, Anabela (Autore) , Costi, Maria P. (Autore) , Venturelli, Alberto (Autore) , Wade, Rebecca C. (Autore)
Natura: Article (Journal)
Lingua:inglese
Pubblicazione: June 8, 2022
In: Journal of medicinal chemistry
Year: 2022, Volume: 65, Fascicolo: 13, Pages: 9011-9033
ISSN:1520-4804
DOI:10.1021/acs.jmedchem.2c00232
Accesso online:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1021/acs.jmedchem.2c00232
Verlag, lizenzpflichtig, Volltext: https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c00232
Testo
Note sull'autore: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
Descrizione
Riassunto: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.
Descrizione del documento:Gesehen am 15.09.2022
Descrizione fisica:Online Resource
ISSN:1520-4804
DOI:10.1021/acs.jmedchem.2c00232

Documenti analoghi