In Silico Identification and in Vitro Activity of Novel Natural Inhibitors of Trypanosoma brucei Glyceraldehyde-3-phosphate-dehydrogenase †
Abstract
:1. Introduction
2. Results and Discussion
2.1. In Silico Prediction of Potential TbGAPDH Inhibitors
2.2. Experimental Validation of TbGAPDH Inhibition
Compound | % Inhibition at c = 50 µM | IC50 (µM) |
---|---|---|
NP-005755 | 44 | |
NP-007496 | n.i. | |
NP-008941 | n.i. | |
NP-010904 | n.i. | |
NP-011694 (1) | 66 | 24.56 ± 1.03 |
NP-012278 | 24 | |
NP-013070 | 33 | |
NP-013296 (2) | 98 | 4.73 ± 1.04 |
NP-013330 (3) | 88 | 21.97 ± 1.03 |
NP-013378 (4) | >90 | 6.68 ± 1.04 |
NP-014428 (5) | >90 | 22.79 ± 1.01 |
NP-015973 | n.i. | |
NP-019430 | 45 |
2.3. Mechanistic Considerations
2.4. In Vitro Antitrypanosomal Activity of Compounds 1–5
Compound | T. brucei rhodesiense (STIB 900) IC50 (µM) | Cytotoxicity (L6) IC50 (µM) | SI |
---|---|---|---|
NP-011694 (1) | 39.5 ± 3.1 | 50.6 ± 3.8 | 1.3 |
NP-013296 (2) | 41.0 ± 0.5 | 48.7 ± 3.8 | 1.2 |
NP-013330 (3) | 17.9 ± 1.6 | 54.2 ± 0.5 | 3.0 |
NP-013378 (4) | 6.7 ± 2.2 | 48.9 ± 4.1 | 7.3 |
NP-014428 (5) | 29.3 ± 6.3 | 15.5 ± 1.8 | 0.5 |
Melarsoprol | 0.005 ± 0.001 | n.t. | n.d. |
Podophyllotoxin | n.t. | 0.019 ± 0.002 | n.d. |
3. Experimental Section
3.1. Database Design
3.2. Acquisition and Preparation of the Proteins’ 3D-Structure
3.3. Pharmacophore Design and Virtual Screening
3.4. Docking Procedures
3.5. Tested Compounds
3.6. Recombinant Expression and Purification of Trypanosoma brucei GAPDH in E. coli
3.7. T. brucei Glyceraldehyde-3-phosphate Dehydrogenase Inhibition Assay
4. Conclusions
Supplementary Materials
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Herrmann, F.C.; Lenz, M.; Jose, J.; Kaiser, M.; Brun, R.; Schmidt, T.J. In Silico Identification and in Vitro Activity of Novel Natural Inhibitors of Trypanosoma brucei Glyceraldehyde-3-phosphate-dehydrogenase. Molecules 2015, 20, 16154-16169. https://doi.org/10.3390/molecules200916154
Herrmann FC, Lenz M, Jose J, Kaiser M, Brun R, Schmidt TJ. In Silico Identification and in Vitro Activity of Novel Natural Inhibitors of Trypanosoma brucei Glyceraldehyde-3-phosphate-dehydrogenase. Molecules. 2015; 20(9):16154-16169. https://doi.org/10.3390/molecules200916154
Chicago/Turabian StyleHerrmann, Fabian C., Mairin Lenz, Joachim Jose, Marcel Kaiser, Reto Brun, and Thomas J. Schmidt. 2015. "In Silico Identification and in Vitro Activity of Novel Natural Inhibitors of Trypanosoma brucei Glyceraldehyde-3-phosphate-dehydrogenase" Molecules 20, no. 9: 16154-16169. https://doi.org/10.3390/molecules200916154