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Comparative mapping of on-targets and off-targets for the discovery of anti-trypanosomatid folate pathway inhibitors.
Panecka-Hofman, Joanna; Pöhner, Ina; Spyrakis, Francesca; Zeppelin, Talia; Di Pisa, Flavio; Dello Iacono, Lucia; Bonucci, Alessio; Quotadamo, Antonio; Venturelli, Alberto; Mangani, Stefano; Costi, Maria Paola; Wade, Rebecca C.
Afiliación
  • Panecka-Hofman J; Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), Schloß-Wolfsbrunnenweg 35, Heidelberg 69118, Germany; Centre of New Technologies (CeNT), University of Warsaw, Banacha 2c, 02-097 Warsaw, Poland. Electronic address: j.panecka@cent.uw.edu.pl.
  • Pöhner I; Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), Schloß-Wolfsbrunnenweg 35, Heidelberg 69118, Germany.
  • Spyrakis F; Department of Drug Science and Technology, University of Turin, Via P. Giuria 9, Turin 10125, Italy; Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, Modena 41121, Italy.
  • Zeppelin T; Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), Schloß-Wolfsbrunnenweg 35, Heidelberg 69118, Germany.
  • Di Pisa F; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, Siena 53100, Italy.
  • Dello Iacono L; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, Siena 53100, Italy.
  • Bonucci A; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, Siena 53100, Italy.
  • Quotadamo A; Tydock Pharma srl, Strada Gherbella 294/B, Modena 41126, Italy.
  • Venturelli A; Tydock Pharma srl, Strada Gherbella 294/B, Modena 41126, Italy.
  • Mangani S; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, Siena 53100, Italy.
  • Costi MP; Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, Modena 41121, Italy.
  • Wade RC; Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), Schloß-Wolfsbrunnenweg 35, Heidelberg 69118, Germany; Center for Molecular Biology (ZMBH), DKFZ-ZMBH Alliance, Heidelberg University, Im Neuenheimer Feld 282, Heidelberg 69120, Germany; Interdisciplinary Cent
Biochim Biophys Acta Gen Subj ; 1861(12): 3215-3230, 2017 Dec.
Article en En | MEDLINE | ID: mdl-28939533
BACKGROUND: Multi-target approaches are necessary to properly analyze or modify the function of a biochemical pathway or a protein family. An example of such a problem is the repurposing of the known human anti-cancer drugs, antifolates, as selective anti-parasitic agents. This requires considering a set of experimentally validated protein targets in the folate pathway of major pathogenic trypanosomatid parasites and humans: (i) the primary parasite on-targets: pteridine reductase 1 (PTR1) (absent in humans) and bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS), (ii) the primary off-targets: human DHFR and TS, and (iii) the secondary on-target: human folate receptor ß, a folate/antifolate transporter. METHODS: We computationally compared the structural, dynamic and physico-chemical properties of the targets. We based our analysis on available inhibitory activity and crystallographic data, including a crystal structure of the bifunctional T. cruzi DHFR-TS with tetrahydrofolate bound determined in this work. Due to the low sequence and structural similarity of the targets analyzed, we employed a mapping of binding pockets based on the known common ligands, folate and methotrexate. RESULTS: Our analysis provides a set of practical strategies for the design of selective trypanosomatid folate pathway inhibitors, which are supported by enzyme inhibition measurements and crystallographic structures. CONCLUSIONS: The ligand-based comparative computational mapping of protein binding pockets provides a basis for repurposing of anti-folates and the design of new anti-trypanosmatid agents. GENERAL SIGNIFICANCE: Apart from the target-based discovery of selective compounds, our approach may be also applied for protein engineering or analyzing evolutionary relationships in protein families.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oxidorreductasas / Timidilato Sintasa / Tripanocidas / Descubrimiento de Drogas / Antagonistas del Ácido Fólico / Complejos Multienzimáticos Límite: Humans Idioma: En Revista: Biochim Biophys Acta Gen Subj Año: 2017 Tipo del documento: Article Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oxidorreductasas / Timidilato Sintasa / Tripanocidas / Descubrimiento de Drogas / Antagonistas del Ácido Fólico / Complejos Multienzimáticos Límite: Humans Idioma: En Revista: Biochim Biophys Acta Gen Subj Año: 2017 Tipo del documento: Article Pais de publicación: Países Bajos