| Autor: |
Maria Kuzikov, G. Landi, Maria Paola Costi, Nuno Santarém, Antonio Quotadamo, Cecilia Pozzi, Ina Poehner, Bernhard Ellinger, Lucia Dello Iacono, Joanna Panecka-Hofman, Stefano Mangani, Matteo Santucci, Rebecca C. Wade, Anabela Cordeiro-da-Silva, Sheraz Gul, Pasquale Linciano, Flavio Di Pisa, Rosaria Luciani, Gesa Witt, Alberto Venturelli |
| Rok vydání: |
2021 |
| Předmět: |
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| Popis: |
The optimization of compounds with multiple targets in the drug discovery cycle is a difficult multidimensional problem. Here, we present a systematic, multidisciplinary approach to the development of selective anti-parasitic compounds. Efficient microwave-assisted synthesis of pteridines along with iterations of crystallographic structure determination were used to validate computational docking predictions and support derivation of a structure-activity relationship for multitarget inhibition. This approach yielded compounds showing picomolar inhibition of T. brucei pteridine reductase 1 (PTR1), nanomolar inhibition of L. major PTR1, along with selective submicromolar inhibition of parasitic dihydrofolate reductase (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, whilst 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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