Structural Insights into the Molecular Design of Flutolanil Derivatives Targeted for Fumarate Respiration of Parasite Mitochondria

International Journal of Molecular Sciences

Daniel Ken Inaoka⁴  Tomoo Shiba¹  Dan Sato¹  Emmanuel Oluwadare Balogun⁴  Tsuyoshi Sasaki¹  Madoka Nagahama¹  Masatsugu Oda³  Shigeru Matsuoka⁵  Junko Ohmori⁴  Teruki Honma²  Masayuki Inoue⁵  Kiyoshi Kita⁴  Shigeharu Harada¹ 

[1] Department of Applied Biology, Graduate School of Science Technology, Kyoto Institute of Technology, Kyoto 606-8585, Japan; E-Mails:;Center for Life Science Technologies, RIKEN, Tsurumi, Yokohama 230-0045, Japan; E-Mail:;Research Center, Nihon Nohyaku Co., Ltd., 345 Oyamada-cho, Kawachinagano, Osaka 586-0094, Japan; E-Mail:;Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; E-Mails:;Department of Integrated Analytical Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan; E-Mails:

关键词: complex II;    NADH-fumarate reductase system;    fumarate respiration;    Ascaris suum;    mitochondria;    flutolanil;    crystal structure;    structure-based drug design;    antiparasitic agent;   

DOI  :  10.3390/ijms160715287

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
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