title: Structural Insights into the Molecular Design of Flutolanil Derivatives Targeted for Fumarate Respiration of Parasite Mitochondria.
abstract: 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.
authors.affiliation: Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan. danielken@m.u-tokyo.ac.jp.
authors.forename: Daniel Ken
authors.initials: DK
authors.lastname: Inaoka
authors.affiliation: Department of Applied Biology, Graduate School of Science Technology, Kyoto Institute of Technology, Kyoto 606-8585, Japan. tshiba@kit.ac.jp.
authors.forename: Tomoo
authors.initials: T
authors.lastname: Shiba
authors.affiliation: Department of Applied Biology, Graduate School of Science Technology, Kyoto Institute of Technology, Kyoto 606-8585, Japan. dsato@kit.ac.jp.
authors.forename: Dan
authors.initials: D
authors.lastname: Sato
authors.affiliation: Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan. balogun1@m.u-tokyo.ac.jp.|Department of Biochemistry, Ahmadu Bello University, Zaria 2222, Nigeria. balogun1@m.u-tokyo.ac.jp.
authors.forename: Emmanuel Oluwadare
authors.initials: EO
authors.lastname: Balogun
authors.affiliation: Department of Applied Biology, Graduate School of Science Technology, Kyoto Institute of Technology, Kyoto 606-8585, Japan. sasaki198603@gmail.com.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Department of Applied Biology, Graduate School of Science Technology, Kyoto Institute of Technology, Kyoto 606-8585, Japan. qp.m.324@gmail.com.
authors.forename: Madoka
authors.initials: M
authors.lastname: Nagahama
authors.affiliation: Research Center, Nihon Nohyaku Co., Ltd., 345 Oyamada-cho, Kawachinagano, Osaka 586-0094, Japan. oda-masatsugu@nichino.co.jp.
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Oda
authors.affiliation: Department of Integrated Analytical Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan. matsuokas11@chem.sci.osaka-u.ac.jp.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Matsuoka
authors.affiliation: Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan. jnk.ohmori@gmail.com.
authors.forename: Junko
authors.initials: J
authors.lastname: Ohmori
authors.affiliation: Center for Life Science Technologies, RIKEN, Tsurumi, Yokohama 230-0045, Japan. honma.teruki@riken.jp.
authors.forename: Teruki
authors.initials: T
authors.lastname: Honma
authors.affiliation: Department of Integrated Analytical Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan. inoue@mol.f.u-tokyo.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Inoue
authors.affiliation: Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan. kitak@m.u-tokyo.ac.jp.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kita
authors.affiliation: Department of Applied Biology, Graduate School of Science Technology, Kyoto Institute of Technology, Kyoto 606-8585, Japan. harada@kit.ac.jp.
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Harada
mesh_terms: D000813:Anilides / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D017165:Ascaris suum / Q000187:drug effects / Q000201:enzymology; D016227:Benzoquinones / Q000378:metabolism; D001665:Binding Sites; D019069:Cell Respiration / Q000187:drug effects; D042963:Electron Transport Complex II / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005650:Fumarates / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008958:Models, Molecular; D010088:Oxidoreductases / Q000378:metabolism; D010271:Parasites / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000378:metabolism; D013379:Substrate Specificity / Q000187:drug effects; D019802:Succinic Acid / Q000378:metabolism; D034421:Sus scrofa
chemical_list: D000813:Anilides; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D005650:Fumarates; C475882:flutolanil; C004532:quinone; D019802:Succinic Acid; D010088:Oxidoreductases; D042963:Electron Transport Complex II; C424907:quinol fumarate reductase; D019764:Phosphoenolpyruvate Carboxykinase (ATP)
keywords: Ascaris suum; NADH-fumarate reductase system; antiparasitic agent; complex II; crystal structure; flutolanil; fumarate respiration; mitochondria; structure-based drug design