Repurposing the Trypanosomatidic GSK Kinetobox for the Inhibition of Parasitic Pteridine and Dihydrofolate Reductases
Abstract
:1. Introduction
2. Results and Discussion
2.1. In Silico Evaluation of Drug-Likeness Properties and Hierarchical Clustering Analysis
2.2. Inhibition of PTR1s and DHFRs
2.3. Molecular Docking
3. Materials and Methods
3.1. Reagents
3.2. In Silico Chemoinformatic and Clustering Analysis
3.3. Protein Purification
3.4. Anti-Kinetoplastid Chemical Boxes
3.4.1. Primary Screening
3.4.2. Secondary Screening (Dose–Response Curve)
3.5. Molecular Modelling
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Physicochemical Property | Minimum Value | Maximum Value | Average | Drug-Likeness Criteria | % Compounds According to RO5 * |
---|---|---|---|---|---|
MW (g/mol) | 210 | 547 | 375 | ≤500 | 99.2% |
AlogP | −2.7 | 5.8 | 2.8 | ≤5 | 98.7% |
HBA | 1 | 8 | 3.8 | ≤10 | 100% |
HBD | 0 | 5 | 1.3 | ≤5 | 100% |
Total Polar Surface Area (Å2) | 19 | 184 | 89.5 | ≤140 | 94.3% |
N° of Rotatable Bonds | 1 | 11 | 5.1 | ≤10 | 99.8% |
| |||||||||
---|---|---|---|---|---|---|---|---|---|
Substituents | IC50 (µM) | EC50 (µM) | |||||||
TCMDC ID | R1 | R2 | HTS_BOX | TbPTR1 | LmPTR1 | TbDHFR | LmDHFR | T. brucei | L. donovani |
143232 | H | | CHAGAS | 10.9 | 5.9 | - | 24.4 | 28.4 | 29.5 |
143295 | CH3 | | LEISH | 7.9 | 6.7 | - | 16.6 | N.D. | 0.06 |
143296 | CH3 | | LEISH | 8.6 | 6.5 | 9.7 | 6.9 | 14.2 | 1.8 |
143297 | CH3 | | LEISH | 9.8 | 5.7 | 11.6 | 20.1 | 35.7 | 0.6 |
143298 | CH3 | | CHAGAS | 8.1 | 6.0 | - | - | 8.8 | 10.8 |
| ||||||||||
---|---|---|---|---|---|---|---|---|---|---|
I | ||||||||||
Substituents | IC50 (µM) | EC50 (µM) | ||||||||
TCMDC ID | R1 | R2 | R3 | HTS_BOX | TbPTR1 | LmPTR1 | TbDHFR | LmDHFR | T. brucei | L. donovani |
143606 (VI) | H | CH2CH3 | (CH2)2CH3 | CHAGAS | 6.4 | 6.8 | - | 19.4 | 22.5 | 27.2 |
143607 (VI) | CH3 | H | | LEISH | 7.3 | 8.1 | - | - | 25.8 | 2.7 |
II | ||||||||||
Substituents | IC50 (µM) | EC50 (µM) | ||||||||
TCMDC ID | R | HTS_BOX | TbPTR1 | LmPTR1 | TbDHFR | LmDHFR | T. brucei | L. donovani | ||
143610 | | CHAGAS | 7.3 | 9.3 | 38.2 | 40.0 | 32.5 | 17.9 | ||
III | ||||||||||
Substituents | IC50 (µM) | EC50 (µM) | ||||||||
TCMDC ID | R | HTS_BOX | TbPTR1 | LmPTR1 | TbDHFR | LmDHFR | T. brucei | L. donovani | ||
143611 (XI) | | CHAGAS | 8.9 | 9.8 | - | - | 5.0 | - |
| |||||||
---|---|---|---|---|---|---|---|
IC50 (µM) | EC50 (µM) | ||||||
TCMDC ID | HTS_BOX | TbPTR1 | LmPTR1 | TbDHFR | LmDHFR | T. brucei | L. donovani |
143191 | CHAGAS | 9.8 | 38.5 | - | - | 39.8 | - |
143249 (XVI) | LEISH | 13.5 | 6.0 | - | - | 6.3 | 5.6 |
143518 (X) | LEISH | 33.3 | 8.5 | - | 25 | 3.8 | 3.5 |
143386 | HAT | 35.0 | 6.7 | - | 25.8 | 0.6 | 1.4 |
143459 | LEISH | 9.8 | - | - | - | 6.6 | 0.5 |
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Santucci, M.; Luciani, R.; Gianquinto, E.; Pozzi, C.; Pisa, F.d.; dello Iacono, L.; Landi, G.; Tagliazucchi, L.; Mangani, S.; Spyrakis, F.; et al. Repurposing the Trypanosomatidic GSK Kinetobox for the Inhibition of Parasitic Pteridine and Dihydrofolate Reductases. Pharmaceuticals 2021, 14, 1246. https://doi.org/10.3390/ph14121246
Santucci M, Luciani R, Gianquinto E, Pozzi C, Pisa Fd, dello Iacono L, Landi G, Tagliazucchi L, Mangani S, Spyrakis F, et al. Repurposing the Trypanosomatidic GSK Kinetobox for the Inhibition of Parasitic Pteridine and Dihydrofolate Reductases. Pharmaceuticals. 2021; 14(12):1246. https://doi.org/10.3390/ph14121246
Chicago/Turabian StyleSantucci, Matteo, Rosaria Luciani, Eleonora Gianquinto, Cecilia Pozzi, Flavio di Pisa, Lucia dello Iacono, Giacomo Landi, Lorenzo Tagliazucchi, Stefano Mangani, Francesca Spyrakis, and et al. 2021. "Repurposing the Trypanosomatidic GSK Kinetobox for the Inhibition of Parasitic Pteridine and Dihydrofolate Reductases" Pharmaceuticals 14, no. 12: 1246. https://doi.org/10.3390/ph14121246