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

  • J Med Chem. 2022 Jul 14;65(13):9011-9033. doi: 10.1021/acs.jmedchem.2c00232.
Ina Pöhner  1  2 ,  Antonio Quotadamo  3  4 ,  Joanna Panecka-Hofman  1  5 ,  Rosaria Luciani  6 ,  Matteo Santucci  6 ,  Pasquale Linciano  6 ,  Giacomo Landi  7 ,  Flavio Di Pisa  7 ,  Lucia Dello Iacono  7 ,  Cecilia Pozzi  7 ,  Stefano Mangani  7 ,  Sheraz Gul  8 ,  Gesa Witt  8 ,  Bernhard Ellinger  8 ,  Maria Kuzikov  8 ,  Nuno Santarem  9 ,  Anabela Cordeiro-da-Silva  9  10 ,  Maria P Costi  6 ,  Alberto Venturelli  3  6 ,  Rebecca C Wade  1  2  11  12
Affiliations
  • 1. Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), D-69118 Heidelberg, Germany.
  • 2. Faculty of Biosciences, Heidelberg University, D-69120 Heidelberg, Germany.
  • 3. Tydock Pharma srl, Strada Gherbella 294/B, 41126 Modena, Italy.
  • 4. Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41121 Modena, Italy.
  • 5. Faculty of Physics, University of Warsaw, 02-093 Warsaw, Poland.
  • 6. Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, 41125 Modena, Italy.
  • 7. Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy.
  • 8. Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, Schnackenburgallee 114, D-22525 Hamburg, Germany.
  • 9. Instituto de Investigação e Inovação em Saúde, Institute for Molecular and Cell Biology, Universidade do Porto, 4200-135 Porto, Portugal.
  • 10. Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
  • 11. Center for Molecular Biology (ZMBH), DKFZ-ZMBH Alliance, Heidelberg University, D-69120 Heidelberg, Germany.
  • 12. Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, D-69120 Heidelberg, Germany.
PMID: 35675511 DOI: 10.1021/acs.jmedchem.2c00232
Abstract

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.

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