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Repurposing the Trypanosomatidic GSK Kinetobox for the Inhibition of Parasitic Pteridine and Dihydrofolate Reductases

Authors :
Costi, Matteo Santucci
Rosaria Luciani
Eleonora Gianquinto
Cecilia Pozzi
Flavio di Pisa
Lucia dello Iacono
Giacomo Landi
Lorenzo Tagliazucchi
Stefano Mangani
Francesca Spyrakis
Maria Paola
Source :
Pharmaceuticals; Volume 14; Issue 12; Pages: 1246
Publication Year :
2021
Publisher :
Multidisciplinary Digital Publishing Institute, 2021.

Abstract

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.

Details

Language :
English
ISSN :
14248247
Database :
OpenAIRE
Journal :
Pharmaceuticals; Volume 14; Issue 12; Pages: 1246
Accession number :
edsair.multidiscipl..9f37c247ef65ec81955c73e3737fb064
Full Text :
https://doi.org/10.3390/ph14121246