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

preprint
submitted on 30.09.2020 and posted on 01.10.2020 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.

Funding

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

History

Email Address of Submitting Author

ina.poehner@h-its.org

Institution

Heidelberg Institute for Theoretical Studies (HITS gGmbH)

Country

Germany

ORCID For Submitting Author

0000-0002-2801-8902

Declaration of Conflict of Interest

The authors declare no competing interests.

Licence

Exports