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

Authors :
Matteo Santucci
Rosaria Luciani
Eleonora Gianquinto
Cecilia Pozzi
Flavio di Pisa
Lucia dello Iacono
Giacomo Landi
Lorenzo Tagliazucchi
Stefano Mangani
Francesca Spyrakis
Maria Paola Costi
Source :
Pharmaceuticals, Vol 14, Iss 12, p 1246 (2021)
Publication Year :
2021
Publisher :
MDPI AG, 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
Volume :
14
Issue :
12
Database :
Directory of Open Access Journals
Journal :
Pharmaceuticals
Publication Type :
Academic Journal
Accession number :
edsdoj.8a1bafe16424b8a3fa4033cb94bf8
Document Type :
article
Full Text :
https://doi.org/10.3390/ph14121246