Ligand-based design, synthesis and biochemical evaluation of potent and selective inhibitors of Schistosoma mansoni dihydroorotate dehydrogenase

David, Juliana S.; Chiappetta, Estela R.C.; Fumagalli, Fernando; Mello, Rodrigo Brito de; Leite, Franco Henrique Andrade; Castilho, Marcelo Santos; Emery, Flávio da Silva; Nonato, Maria Cristina

doi:10.1016/j.ejmech.2019.02.018

Cited by 18 publications

(20 citation statements)

References 37 publications

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“…We also investigate the effect of the removal of this protuberant domain in inhibitor binding. Since Sm DHODHΔloop was found inactive, we applied differential scanning fluorimetry (ThermoFMN, [35]) on both constructs to compare the thermal stability effects with IC 50 against our library of atovaquone analogues [30] (Figs 2 and 7).…”

Section: Resultsmentioning

confidence: 99%

“…Sm DHODH crystals were obtained in complex with QLA, a simplified analogue of atovaquone, and previously identified Sm DHODH inhibitor [30] (Fig. 8).…”

Section: Resultsmentioning

confidence: 99%

“…Ser 53 , which stabilizes the hydroxynaphthoquinone moiety by a hydrogen bond with its hydroxyl group (Oγ from Ser 53 and O2 from QLA), helps to generate a more polar environment in the parasitic enzyme when compared to the homologous human enzyme. The interaction between Ser 53 and the hydroxyl group of QLA revealed to be essential for inhibition since substitutions in this position display low inhibitory activity (Figs 2 and 7) [30]. The polar nature of Ser 53 is also responsible for pushing away the fluorophenyl ring toward helix α in the QLA‐ Sm DHODH complex.…”

Section: Resultsmentioning

confidence: 99%

“…Those results prompted to us the idea of exploiting atovaquone and its analogues to both validate DHODH as a drug target and search for drug leads against schistosomiasis. Thus, a series of quinones (atovaquone analogues) was evaluated regarding potency and selectivity against both Sm DHODH and human DHODH [30]. Those studies allowed us to identify low nanomolar inhibitors, that together with atovaquone, are currently being evaluated with respect to their antischistosomal activity.…”

Section: Introductionmentioning

confidence: 99%

“…As an important step toward mapping the structural basis that confers potency and selectivity for these series of inhibitors, we now move forward and solved the first crystal structure of Sm DHODH in complex with the previously identified inhibitor 2‐((4‐fluorophenyl)amino)‐3‐hydroxynaphthalene‐1,4‐dione (QLA) [30]. The crystal structure of Sm DHODH contains the canonical overall α/β barrel fold found in all DHODHs [18] and the small N‐terminal alpha‐helical domain that serves as the binding site for class 2 DHODH inhibitors, including QLA.…”

Section: Introductionmentioning

confidence: 99%

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Structural basis for the function and inhibition of dihydroorotate dehydrogenase from Schistosoma mansoni

et al. 2020

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Schistosomiasis is a serious public health problem, prevalent in tropical and subtropical areas, especially in poor communities without access to safe drinking water and adequate sanitation. Transmission has been reported in 78 countries, and its control depends on a single drug, praziquantel, which has been used over the past 30 years. Our work is focused on exploiting target‐based drug discovery strategies to develop new therapeutics to treat schistosomiasis. In particular, we are interested in evaluating the enzyme dihydroorotate dehydrogenase (DHODH) as a drug target. DHODH is a flavoenzyme that catalyzes the stereospecific oxidation of (S)‐dihydroorotate (DHO) to orotate during the fourth and only redox step of the de novo pyrimidine nucleotide biosynthetic pathway. Previously, we identified atovaquone, used in the treatment of malaria, and its analogues, as potent and selective inhibitors against Schistosoma mansoni DHODH (SmDHODH). In the present article, we report the first crystal structure of SmDHODH in complex with the atovaquone analogue inhibitor 2‐((4‐fluorophenyl)amino)‐3‐hydroxynaphthalene‐1,4‐dione (QLA). We discuss three major findings: (a) the open conformation of the active site loop and the unveiling of a novel transient druggable pocket for class 2 DHODHs; (b) the presence of a protuberant domain, only present in Schistosoma spp DHODHs, that was found to control and modulate the dynamics of the inhibitor binding site; (c) a detailed description of an unexpected binding mode for the atovaquone analogue to SmDHODH. Our findings contribute to the understanding of the catalytic mechanism performed by class 2 DHODHs and provide the molecular basis for structure‐guided design of SmDHODH inhibitors. Database The structural data are available in Protein Data Bank (PDB) database under the accession code number https://www.rcsb.org/structure/6UY4.

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Section: Resultsmentioning

confidence: 99%

“…Sm DHODH crystals were obtained in complex with QLA, a simplified analogue of atovaquone, and previously identified Sm DHODH inhibitor [30] (Fig. 8).…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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