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.
Highlights
Introduction published maps and institutional affilNeglected tropical diseases (NTDs) are a diverse set of 20 diseases that cause a devastating human, social and economic burden on more than 1 billion people worldwide, predominantly in tropical and subtropical areas [1]
We found that the results obtained from the docking analysis of the 14 compounds against the LmDHFR-TS model agree with the observed experimental data
Val156 are a π–π and hydrophobic ported below, we found that the results obtained from the docking analysis of the 14 co pounds against the LmDHFR-TS model agree with the observed experimental data
Summary
Neglected tropical diseases (NTDs) are a diverse set of 20 diseases that cause a devastating human, social and economic burden on more than 1 billion people worldwide, predominantly in tropical and subtropical areas [1]. Trypanosomatids are single-celled protozoan parasites, which cause various diseases such as Leishmaniasis, Chagas disease and human African trypanosomiasis (HAT), all known as vector borne parasitic diseases [2,3]. The treatment with currently available drugs, discovered decades ago, presents many drawbacks, such as high toxicity, poor efficacy, difficulties in administration and drug resistance [5,6,7,8,9]. There is an urgent need to discover new, improved and affordable drugs as well as promising drug targets for the design of new antiparasitic compounds. There is an urgent need to discover new, improved and affordable drugs as well as promising drug targets for the design of new antiparasitic compounds. iations.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
