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

Inaoka, Daniel Ken; Shiba, T.; Sato, Dan; Balogun, E.O.; Sasaki, Tsuyoshi; Nagahama, Madoka; Oda, Masaaki; Matsuoka, Shigeru; Ohmori, Junko; Honma, Teruki; Inoue, M.; Kita, Kiyoshi; Harada, Shigeharu

doi:10.3390/ijms160715287

Cited by 68 publications

(65 citation statements)

References 41 publications

(51 reference statements)

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“…(b) Structures representing MDH: 1BMD, in complex with NAD þ (40) , 2CMD, in complex with CIT (31) , 1B8U, in complex with NAD þ (43) , 1EMD, in complex with NAD þ and CIT (30) , 1Y7T, in complex with NADPH (74) , 1BDM, in complex with NAD þ (40) and 1IE3, in complex with NAD þ and PYR (6) . (c) Structures representing SDH: 1YQ3, in complex with FAD and UBQ (33) , 1NEK, in complex with FAD (84) , 1NEN, in complex with dinitrophenol-17 inhibitor ubiquinone binding site (84) , 4YXD, in complex with FTN (35) and 1ZOY, in complex with FAD and UBQ1 (71) .…”

Section: Molecular Docking Structural Analyses and Interaction Energmentioning

confidence: 99%

Tricarboxylic acid cycle dehydrogenases inhibition by naringenin: experimental and molecular modelling evidence

et al. 2020

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The study of polyphenols’ effects on health has been gaining attention lately. In addition to reacting with important enzymes, altering the cell metabolism, these substances can present either positive or negative metabolic alterations depending on their consumption levels. Naringenin, a citrus flavonoid, already presents diverse metabolic effects. The objective of this work was to evaluate the effect of maternal naringenin supplementation during pregnancy on the tricarboxylic acid cycle activity in offspring’s cerebellum. Adult female Wistar rats were divided into two groups: (1) vehicle (1 ml/kg by oral administration (p.o.)) or (2) naringenin (50 mg/kg p.o.). The offspring were euthanised at 7th day of life, and the cerebellum was dissected to analyse citrate synthase, isocitrate dehydrogenase (IDH), α-ketoglutarate dehydrogenase (α-KGDH) and malate dehydrogenase (MDH) activities. Molecular docking used SwissDock web server and FORECASTER Suite, and the proposed binding pose image was created on UCSF Chimera. Data were analysed by Student’s t test. Naringenin supplementation during pregnancy significantly inhibited IDH, α-KGDH and MDH activities in offspring’s cerebellum. A similar reduction was observed in vitro, using purified α-KGDH and MDH, subjected to pre-incubation with naringenin. Docking simulations demonstrated that naringenin possibly interacts with dehydrogenases in the substrate and cofactor binding sites, inhibiting their function. Naringenin administration during pregnancy may affect cerebellar development and must be evaluated with caution by pregnant women and their physicians.

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Section: Molecular Docking Structural Analyses and Interaction Energmentioning

confidence: 99%

Tricarboxylic acid cycle dehydrogenases inhibition by naringenin: experimental and molecular modelling evidence

et al. 2020

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“…suum is a suitable model for biochemical studies of mitochondrial NADH-fumarate reductase systems because the body sizes of adult worms are easy to manipulate. We previously reported that the NADH-fumarate reductase system is a good target for the development of novel, selective anthelmintic compounds as modeled in A. suum [38,39]. It is composed of complex I (NADH-quinone reductase, NQR), complex II (quinol-fumarate reductase, QFR), and a low-potential electron mediator, rhodoquinone (RQ).…”

Section: Nadh-fumarate Reductase System (Fumarate Respiration)mentioning

confidence: 99%

“…Flutolanil and atpenin A5 are known effective inhibitors of the quinone-binding site of A. suum complex II [42,43]. Elucidation of crystal structures of A. suum complex II in the presence of flutolanil provided useful information for the structure-based design of a more effective inhibitor [39,44]. As a crystallographic analysis of Echinococcus complex II is challenging, we conducted comparative analyses of E. multilocularis with other parasites and host enzymes.…”

Section: Echinococcosis 52mentioning

confidence: 99%

“…The IC 50 and selectivity index of flutolanil for A. suum were 58 nM and 762, respectively. The flutolanil-binding site is located at the RQ-binding pocket, which is formed at the interface domain composed of three subunits, Ip, CybL, and CybS [39,44]. Moreover, CH-π interaction between flutolanil isopropyl group and tryptophan69 (Trp) in CybL is one of the significant factors for the highly specific inhibitory effects of flutolanil against A. suum complex II [44].…”

Section: Inhibition Of Complex II By a Quinone-binding Site Inhibitormentioning

confidence: 99%

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Medical Treatment of Echinococcus multilocularis and New Horizons for Drug Discovery: Characterization of Mitochondrial Complex II as a Potential Drug Target

Enkai¹,

Sakamoto²,

Kaneko³

et al. 2017

Echinococcosis

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As an efficient drug for alveolar echinococcosis (AE) is still not available, new chemotherapy targets are necessary. The mitochondrial respiratory chain may be a good drug candidate because parasite respiratory chains are quite different from those of mammalian hosts. For example, Ascaris suum possesses an NADH-fumarate reductase system (fumarate respiration) that is highly adapted to anaerobic environments such as the small intestine. It is composed of mitochondrial complex I (NADH-ubiquinone reductase), complex II (succinate-ubiquinone reductase), and rhodoquinone. We previously demonstrated that fumarate respiration is also essential in E. multilocularis. Quinazoline, a complex I inhibitor, inhibited growth of E. multilocularis larvae in vitro. These results indicate that fumarate respiration could be a target for E. multilocularis therapy. In the current chapter, we focused on complex II, which is another component of this system, because quinazoline exhibited strong toxicity to mammalian mitochondria. We evaluated the molecular and biochemical characterization of E. multilocularis complex II as a potential drug target. In addition, we found that ascofuranone, a trypanosome cyanide-insensitive alternative oxidase inhibitor, inhibited E. multilocularis complex II at the nanomolar order. Our findings demonstrate the potential development of targeted therapy against Echinococcus complex II.

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“…Previously, we reported the crystal structures of TAO in complex with ascofuranone derivatives (3VVA and 3W54)[27] as well as A . suum QFR in complex with flutolanil (3VR9 and 3VRB)[28] , [29] , [30], its derivatives (4YSZ, 4YT0, 4YTM, 4YSX and 4YSY) and the substrate rhodoquinone (5C2T)[31], providing structural insights into their inhibition mechanisms. Both type of inhibitors bind to the quinol binding site of each target.…”

Section: Introductionmentioning

confidence: 99%

The Open Form Inducer Approach for Structure-Based Drug Design

et al. 2016

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Many open form (OF) structures of drug targets were obtained a posteriori by analysis of co-crystals with inhibitors. Therefore, obtaining the OF structure of a drug target a priori will accelerate development of potent inhibitors. In addition to its small active site, Trypanosoma cruzi dihydroorotate dehydrogenase (TcDHODH) is fully functional in its monomeric form, making drug design approaches targeting the active site and protein-protein interactions unrealistic. Therefore, a novel a priori approach was developed to determination the TcDHODH active site in OF. This approach consists of generating an "OF inducer" (predicted in silico) to bind the target and cause steric repulsion with flexible regions proximal to the active site that force it open. We provide the first proof-of-concept of this approach by predicting and crystallizing TcDHODH in complex with an OF inducer, thereby obtaining the OF a priori with its subsequent use in designing potent and selective inhibitors. Fourteen co-crystal structures of TcDHODH with the designed inhibitors are presented herein. This approach has potential to encourage drug design against diseases where the molecular targets are such difficult proteins possessing small AS volume. This approach can be extended to study open/close conformation of proteins in general, the identification of allosteric pockets and inhibitors for other drug targets where conventional drug design approaches are not applicable, as well as the effective exploitation of the increasing number of protein structures deposited in Protein Data Bank.

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

Cited by 68 publications

References 41 publications

Tricarboxylic acid cycle dehydrogenases inhibition by naringenin: experimental and molecular modelling evidence

Tricarboxylic acid cycle dehydrogenases inhibition by naringenin: experimental and molecular modelling evidence

Medical Treatment of Echinococcus multilocularis and New Horizons for Drug Discovery: Characterization of Mitochondrial Complex II as a Potential Drug Target

The Open Form Inducer Approach for Structure-Based Drug Design

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