Trypanothione reductase: a target protein for a combined in vitro and in silico screening approach
| Autor: | Frank Oellien, Paul M. Selzer, Sandra Noack, Linnéa Garoff, Mathias Beig, R. Luise Krauth-Siegel |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Models
Molecular lcsh:Arctic medicine. Tropical medicine Spermidine lcsh:RC955-962 High-throughput screening In silico Trypanosoma cruzi Drug Evaluation Preclinical Protozoan Proteins Biology Inhibitory Concentration 50 Chagas Disease Computer Simulation NADH NADPH Oxidoreductases Enzyme kinetics Enzyme Inhibitors Trypanocidal agent Drug discovery lcsh:Public aspects of medicine Chlorhexidine Public Health Environmental and Occupational Health lcsh:RA1-1270 biology.organism_classification Molecular biology Glutathione Trypanocidal Agents In vitro 3. Good health Kinetics Infectious Diseases Biochemistry Quinacrine Target protein Research Article |
| Zdroj: | PLoS Neglected Tropical Diseases, Vol 9, Iss 6, p e0003773 (2015) PLoS Neglected Tropical Diseases |
| ISSN: | 1935-2735 1935-2727 |
| Popis: | With the goal to identify novel trypanothione reductase (TR) inhibitors, we performed a combination of in vitro and in silico screening approaches. Starting from a highly diverse compound set of 2,816 compounds, 21 novel TR inhibiting compounds could be identified in the initial in vitro screening campaign against T. cruzi TR. All 21 in vitro hits were used in a subsequent similarity search-based in silico screening on a database containing 200,000 physically available compounds. The similarity search resulted in a data set containing 1,204 potential TR inhibitors, which was subjected to a second in vitro screening campaign leading to 61 additional active compounds. This corresponds to an approximately 10-fold enrichment compared to the initial pure in vitro screening. In total, 82 novel TR inhibitors with activities down to the nM range could be identified proving the validity of our combined in vitro/in silico approach. Moreover, the four most active compounds, showing IC50 values of Author Summary Trypanosomatidae are responsible for approximately half a million human fatalities per annum and the situation is compounded by substantial economic losses due to affecting live stock as well. Trypanothione reductase (TR) is an essential key enzyme of the unique trypanothione-based thiol metabolism of the trypanosomatidae and TR is a promising target for the development of selective inhibitors. However, TR is a very hard to attack target in standard drug discovery approaches. Therefore, we developed a combined and iterative in vitro and in silico screening approach, which led to a high number of novel TR inhibitors. 82 of those showed activities down to the nM range against T. cruzi TR. Moreover, the four most active compounds were selected for determining the inhibitor constant. In first on parasite efficacy studies, three of those compounds inhibited the proliferation of bloodstream T. brucei cell line 449 with EC50 values down to 2 μM. |
| Databáze: | OpenAIRE |
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