2. Academic Validation
  3. Multitarget, Selective Compound Design Yields Potent Inhibitors of a Kinetoplastid Pteridine Reductase 1

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

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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