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Multitarget, Selective Compound Design Yields Picomolar Inhibitors of a Kinetoplastid Pteridine Reductase 1

revised on 23.11.2020, 11:04 and posted on 23.11.2020, 12:24 by Ina Poehner, 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 Paola Costi, Alberto Venturelli, Rebecca Wade
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.


European Union's Seventh Framework Programme for research, technological development and demonstration grant agreement no 603240

Klaus Tschira Foundation

Polish National Science Centre (grant no. 2016/21/D/NZ1/02806)

BIOMS program at the Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University


Email Address of Submitting Author


Heidelberg Institute for Theoretical Studies (HITS gGmbH)



ORCID For Submitting Author


Declaration of Conflict of Interest

The authors declare no competing interests.