Identification of New Antifungal Compounds Targeting Thioredoxin Reductase of Paracoccidioides Genus

Abadio, Ana Karina Rodrigues; Kioshima, Érika Seki; Leroux, Vincent; Martins, N. F.; Maigret, Bernard; Felipe, Maria Sueli Soares

doi:10.1371/journal.pone.0142926

Cited by 27 publications

(28 citation statements)

References 83 publications

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“…Three compounds were identified and tests against purified Paracoccidioides Trr protein confirmed the compound inhibited Trr enzymatic activity. 97 Phenotype tests demonstrated that 2 compounds had significant biological activity against Paracoccidioides yeasts with MICs of 8-16 mg/mL (compounds F1806-0122 and F3307-0100). This study validates target based screening as an approach to identification of potential antifungal compounds.…”

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confidence: 99%

Antifungal therapeutics for dimorphic fungal pathogens

Goughenour

Rappleye

2016

Virulence

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Dimorphic fungi cause several endemic mycoses which range from subclinical respiratory infections to life-threatening systemic disease. Pathogenic-phase cells of Histoplasma, Blastomyces, Paracoccidioides and Coccidioides escape elimination by the innate immune response with control ultimately requiring activation of cell-mediated immunity. Clinical management of disease relies primarily on antifungal compounds; however, dimorphic fungal pathogens create a number of challenges for antifungal drug therapy. In addition to the drug toxicity issues known for current antifungals, barriers to efficient drug treatment of dimorphic fungal infections include natural resistance to the echinocandins, residence of fungal cells within immune cells, the requirement for systemic delivery of drugs, prolonged treatment times, potential for latent infections, and lack of optimized standardized methodology for in vitro testing of drug susceptibilities. This review will highlight recent advances, current therapeutic options, and new compounds on the horizon for treating infections by dimorphic fungal pathogens.

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confidence: 99%

Antifungal therapeutics for dimorphic fungal pathogens

Goughenour

Rappleye

2016

Virulence

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“…Abadio et al (26) selected three molecules targeting the enzyme thioredoxin reductase by virtual screening, the same technique used in this study. These three molecules exhibited MIC values of 8 to Ͼ256 g · ml Ϫ1 and 16 to Ͼ256 g · ml Ϫ1 for strains of P. brasiliensis and P. lutzii, respectively.…”

Section: Fig 4 In Vitro Cytotoxicity For Hela Cells Compounds Hs1 (Amentioning

confidence: 99%

“…According to Abadio et al (26), the toxicities and drug interactions observed with contemporary antifungal therapies can be attributed to, among other causes, nonselective interactions with enzymes or cell membrane systems found in the mammalian host. Therefore, the search for new and more specific drugs that minimize the serious problem of side effects remains a major challenge (22,26).…”

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confidence: 99%

Targeting the Homoserine Dehydrogenase of Paracoccidioides Species for Treatment of Systemic Fungal Infections

Bagatin

Pimentel

Biavatti

et al. 2017

Antimicrob Agents Chemother

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This work evaluated new potential inhibitors of the enzyme homoserine dehydrogenase (HSD) of Paracoccidioides brasiliensis, one of the etiological agents of paracoccidioidomycosis. The tertiary structure of the protein bonded to the analogue NAD, and L-homoserine was modeled by homology. The model with the best output was subjected to gradient minimization, redocking, and molecular dynamics simulation. Virtual screening simulations with 187,841 molecules purchasable from the Zinc database were performed. After the screenings, 14 molecules were selected and analyzed by the use of absorption, distribution, metabolism, excretion, and toxicity criteria, resulting in four compounds for in vitro assays. The molecules HS1 and HS2 were promising, exhibiting MICs of 64 and 32 g · ml Ϫ1 , respectively, for the Pb18 isolate of P. brasilensis, 64 g · ml Ϫ1 for two isolates of P. lutzii, and also synergy with itraconazole. The application of these molecules to human-pathogenic fungi confirmed that the HSD enzyme may be used as a target for the development of drugs with specific action against paracoccidioidomycosis; moreover, these compounds may serve as leads in the design of new antifungals.

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“…Red letters 1JFA helices as assigned by the define secondary structure of proteins (DSSP) algorithm chemical providers using the ChemicalAssistant software [36,37]. Through diversity information, we obtained the most suitable library for the VS experiment in order to find putative longiborneol synthase inhibitors [38].…”

Section: Virtual Screeningmentioning

confidence: 99%

“…The structural similarity of the selected compounds was evaluated by the Tanimoto index [31,38,46]. The scores were obtained by Purple α -helices, yellow β-sheets, blue 3 10 -helices, green turns, white coils Open Babel using the FP2 fingerprint [47].…”

Section: Virtual Screeningmentioning

confidence: 99%

Structure-based virtual screening of hypothetical inhibitors of the enzyme longiborneol synthase—a potential target to reduce Fusarium head blight disease

Bresso

Leroux²,

Urban

et al. 2016

J Mol Model

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Fusarium head blight (FHB) is one of the most destructive diseases of wheat and other cereals worldwide. During infection, the Fusarium fungi produce mycotoxins that represent a high risk to human and animal health. Developing small-molecule inhibitors to specifically reduce mycotoxin levels would be highly beneficial since current treatments unspecifically target the Fusarium pathogen. Culmorin possesses a well-known important synergistically virulence role among mycotoxins, and longiborneol synthase appears to be a key enzyme for its synthesis, thus making longiborneol synthase a particularly interesting target. This study aims to discover potent and less toxic agrochemicals against FHB. These compounds would hamper culmorin synthesis by inhibiting longiborneol synthase. In order to select starting molecules for further investigation, we have conducted a structure-based virtual screening investigation. A longiborneol synthase structural model is first built using homology modeling, followed by molecular dynamics simulations that provided the required input for a protein-ligand ensemble docking procedure. From this strategy, the three most interesting compounds (hits) were selected among the 25 top-ranked docked compounds from a library of 15,000 drug-like compounds. These putative inhibitors of longiborneol synthase provide a sound starting point for further studies involving molecular modeling coupled to biochemical experiments. This process could eventually lead to the development of novel approaches to reduce mycotoxin contamination in harvested grain.

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Identification of New Antifungal Compounds Targeting Thioredoxin Reductase of Paracoccidioides Genus

Cited by 27 publications

References 83 publications

Antifungal therapeutics for dimorphic fungal pathogens

Antifungal therapeutics for dimorphic fungal pathogens

Targeting the Homoserine Dehydrogenase of Paracoccidioides Species for Treatment of Systemic Fungal Infections

Structure-based virtual screening of hypothetical inhibitors of the enzyme longiborneol synthase—a potential target to reduce Fusarium head blight disease

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