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Repurposing the Trypanosomatidic GSK Kinetobox for the Inhibition of Parasitic Pteridine and Dihydrofolate Reductases
Three open-source anti-kinetoplastid chemical boxes derived from a whole-cell phenotypic screening by GlaxoSmithKline (Tres Cantos Anti-Kinetoplastid Screening, TCAKS) were exploited for the discovery of a novel core structure inspiring new treatments of parasitic diseases targeting the trypansosmat...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8704748/ https://www.ncbi.nlm.nih.gov/pubmed/34959646 http://dx.doi.org/10.3390/ph14121246 |
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author | Santucci, Matteo Luciani, Rosaria Gianquinto, Eleonora Pozzi, Cecilia Pisa, Flavio di dello Iacono, Lucia Landi, Giacomo Tagliazucchi, Lorenzo Mangani, Stefano Spyrakis, Francesca Costi, Maria Paola |
author_facet | Santucci, Matteo Luciani, Rosaria Gianquinto, Eleonora Pozzi, Cecilia Pisa, Flavio di dello Iacono, Lucia Landi, Giacomo Tagliazucchi, Lorenzo Mangani, Stefano Spyrakis, Francesca Costi, Maria Paola |
author_sort | Santucci, Matteo |
collection | PubMed |
description | Three open-source anti-kinetoplastid chemical boxes derived from a whole-cell phenotypic screening by GlaxoSmithKline (Tres Cantos Anti-Kinetoplastid Screening, TCAKS) were exploited for the discovery of a novel core structure inspiring new treatments of parasitic diseases targeting the trypansosmatidic pteridine reductase 1 (PTR1) and dihydrofolate reductase (DHFR) enzymes. In total, 592 compounds were tested through medium-throughput screening assays. A subset of 14 compounds successfully inhibited the enzyme activity in the low micromolar range of at least one of the enzymes from both Trypanosoma brucei and Lesihmania major parasites (pan-inhibitors), or from both PTR1 and DHFR-TS of the same parasite (dual inhibitors). Molecular docking studies of the protein–ligand interaction focused on new scaffolds not reproducing the well-known antifolate core clearly explaining the experimental data. TCMDC-143249, classified as a benzenesulfonamide derivative by the QikProp descriptor tool, showed selective inhibition of PTR1 and growth inhibition of the kinetoplastid parasites in the 5 μM range. In our work, we enlarged the biological profile of the GSK Kinetobox and identified new core structures inhibiting selectively PTR1, effective against the kinetoplastid infectious protozoans. In perspective, we foresee the development of selective PTR1 and DHFR inhibitors for studies of drug combinations. |
format | Online Article Text |
id | pubmed-8704748 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-87047482021-12-25 Repurposing the Trypanosomatidic GSK Kinetobox for the Inhibition of Parasitic Pteridine and Dihydrofolate Reductases Santucci, Matteo Luciani, Rosaria Gianquinto, Eleonora Pozzi, Cecilia Pisa, Flavio di dello Iacono, Lucia Landi, Giacomo Tagliazucchi, Lorenzo Mangani, Stefano Spyrakis, Francesca Costi, Maria Paola Pharmaceuticals (Basel) Article Three open-source anti-kinetoplastid chemical boxes derived from a whole-cell phenotypic screening by GlaxoSmithKline (Tres Cantos Anti-Kinetoplastid Screening, TCAKS) were exploited for the discovery of a novel core structure inspiring new treatments of parasitic diseases targeting the trypansosmatidic pteridine reductase 1 (PTR1) and dihydrofolate reductase (DHFR) enzymes. In total, 592 compounds were tested through medium-throughput screening assays. A subset of 14 compounds successfully inhibited the enzyme activity in the low micromolar range of at least one of the enzymes from both Trypanosoma brucei and Lesihmania major parasites (pan-inhibitors), or from both PTR1 and DHFR-TS of the same parasite (dual inhibitors). Molecular docking studies of the protein–ligand interaction focused on new scaffolds not reproducing the well-known antifolate core clearly explaining the experimental data. TCMDC-143249, classified as a benzenesulfonamide derivative by the QikProp descriptor tool, showed selective inhibition of PTR1 and growth inhibition of the kinetoplastid parasites in the 5 μM range. In our work, we enlarged the biological profile of the GSK Kinetobox and identified new core structures inhibiting selectively PTR1, effective against the kinetoplastid infectious protozoans. In perspective, we foresee the development of selective PTR1 and DHFR inhibitors for studies of drug combinations. MDPI 2021-11-30 /pmc/articles/PMC8704748/ /pubmed/34959646 http://dx.doi.org/10.3390/ph14121246 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Santucci, Matteo Luciani, Rosaria Gianquinto, Eleonora Pozzi, Cecilia Pisa, Flavio di dello Iacono, Lucia Landi, Giacomo Tagliazucchi, Lorenzo Mangani, Stefano Spyrakis, Francesca Costi, Maria Paola Repurposing the Trypanosomatidic GSK Kinetobox for the Inhibition of Parasitic Pteridine and Dihydrofolate Reductases |
title | Repurposing the Trypanosomatidic GSK Kinetobox for the Inhibition of Parasitic Pteridine and Dihydrofolate Reductases |
title_full | Repurposing the Trypanosomatidic GSK Kinetobox for the Inhibition of Parasitic Pteridine and Dihydrofolate Reductases |
title_fullStr | Repurposing the Trypanosomatidic GSK Kinetobox for the Inhibition of Parasitic Pteridine and Dihydrofolate Reductases |
title_full_unstemmed | Repurposing the Trypanosomatidic GSK Kinetobox for the Inhibition of Parasitic Pteridine and Dihydrofolate Reductases |
title_short | Repurposing the Trypanosomatidic GSK Kinetobox for the Inhibition of Parasitic Pteridine and Dihydrofolate Reductases |
title_sort | repurposing the trypanosomatidic gsk kinetobox for the inhibition of parasitic pteridine and dihydrofolate reductases |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8704748/ https://www.ncbi.nlm.nih.gov/pubmed/34959646 http://dx.doi.org/10.3390/ph14121246 |
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