Structural Insights into the Molecular Design of Flutolanil Derivatives Targeted for Fumarate Respiration of Parasite Mitochondria
| Autor: | Teruki Honma, Tsuyoshi Sasaki, Emmanuel Oluwadare Balogun, Dan Sato, Junko Ohmori, Madoka Nagahama, Masatsugu Oda, Shigeru Matsuoka, Tomoo Shiba, Kiyoshi Kita, Shigeharu Harada, Masayuki Inoue, Daniel Ken Inaoka |
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| Rok vydání: | 2015 |
| Předmět: |
Models
Molecular NADH-fumarate reductase system Sus scrofa Succinic Acid Respiratory chain Mitochondrion fumarate respiration Substrate Specificity lcsh:Chemistry Fumarates Benzoquinones Anilides Enzyme Inhibitors lcsh:QH301-705.5 Ascaris suum Spectroscopy chemistry.chemical_classification biology Electron Transport Complex II General Medicine respiratory system Mitochondria Computer Science Applications Biochemistry flutolanil Oxidoreductases crystal structure Cell Respiration antiparasitic agent Article Catalysis Inorganic Chemistry parasitic diseases Animals Parasites Physical and Theoretical Chemistry Binding site Molecular Biology Binding Sites complex II Organic Chemistry biology.organism_classification Antiparasitic agent Enzyme lcsh:Biology (General) lcsh:QD1-999 chemistry Structural biology structure-based drug design Phosphoenolpyruvate Carboxykinase (ATP) |
| Zdroj: | International Journal of Molecular Sciences Volume 16 Issue 7 Pages 15287-15308 International Journal of Molecular Sciences, Vol 16, Iss 7, Pp 15287-15308 (2015) |
| ISSN: | 1422-0067 |
| Popis: | Recent studies on the respiratory chain of Ascaris suum showed that the mitochondrial NADH-fumarate reductase system composed of complex I, rhodoquinone and complex II plays an important role in the anaerobic energy metabolism of adult A. suum. The system is the major pathway of energy metabolism for adaptation to a hypoxic environment not only in parasitic organisms, but also in some types of human cancer cells. Thus, enzymes of the pathway are potential targets for chemotherapy. We found that flutolanil is an excellent inhibitor for A. suum complex II (IC50 = 0.058 μM) but less effectively inhibits homologous porcine complex II (IC50 = 45.9 μM). In order to account for the specificity of flutolanil to A. suum complex II from the standpoint of structural biology, we determined the crystal structures of A. suum and porcine complex IIs binding flutolanil and its derivative compounds. The structures clearly demonstrated key interactions responsible for its high specificity to A. suum complex II and enabled us to find analogue compounds, which surpass flutolanil in both potency and specificity to A. suum complex II. Structures of complex IIs binding these compounds will be helpful to accelerate structure-based drug design targeted for complex IIs. |
| Databáze: | OpenAIRE |
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