Computer-aided identification of novel anti-paracoccidioidomycosis compounds

Silva, Lívia C; Neves, Bruno J.; Gomes, Marcelo N.; Melo-Filho, Cleber C.; Soares, C. M. A.; Andrade, Carolina Horta; Pereira, Maristela

doi:10.2217/fmb-2018-0175

Cited by 15 publications

(12 citation statements)

References 35 publications

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“…Virtual screening based on the ligand or structure target is being performed in the identification of new compounds for PCM treatment [20, 29, 34]. The thioredoxin reductase (Trr1) has been shown as an important target for the development of molecules with antifungal activity [16, 35].…”

Section: Discussionmentioning

confidence: 99%

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Antifungal activity of two oxadiazole compounds for the paracoccidioidomycosis treatment

Rodrigues-Vendramini¹,

Faria²,

Arita³

et al. 2019

PLoS Negl Trop Dis

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Paracoccidioidomycosis (PCM) is a neglected disease present in Latin America with difficulty in treatment and occurrence of serious sequelae. Thus, the development of alternative therapies is imperative. In the current work, two oxadiazole compounds (LMM5 and LMM11) presented fungicidal activity against Paracoccidioides spp. The minimum inhibitory and fungicidal concentration values ranged from 1 to 32 μg/mL, and a synergic effect was observed for both compounds when combined with Amphotericin B. LMM5 and LMM11 were able to reduce CFU counts (�2 log 10) on the 5 th and 7 th days of time-kill curve, respectively. The fungicide effect was confirmed by fluorescence microscopy (FUN-1/FUN-2). The hippocratic screening and biochemical analysis were performed in Balb/c male mice that received a high dose of each compound, and the compounds showed no in vivo toxicity. The treatment of experimental PCM with the new oxadiazoles led to significant reduction in CFU (�1 log 10). Histopathological analysis of the groups treated exhibited control of inflammation, as well as preserved lung areas. These findings suggest that LMM5 and LMM11 are promising hits structures, opening the door for implementing new PCM therapies.

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Section: Discussionmentioning

confidence: 99%

“…showed MIC values between 3.90 and 62.50 μg/mL [39]. In addition, new chalcone derivatives presented antifungal activity with MIC values between 2.9 and 42.2 μM [34].…”

Section: Discussionmentioning

confidence: 99%

Antifungal activity of two oxadiazole compounds for the paracoccidioidomycosis treatment

Rodrigues-Vendramini¹,

Faria²,

Arita³

et al. 2019

PLoS Negl Trop Dis

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“…Pb 01, Pb 18, and Pb 03 cells were exposed to the same concentration of the target drugs and the culture conditions used for the MIC test. From each well, 20 μL of culture was transferred to solidified Fava-Netto medium (Silva et al, 2018). The plates were incubated at 37°C for 7 days.…”

Section: Methodsmentioning

confidence: 99%

Drug Repurposing for Paracoccidioidomycosis Through a Computational Chemogenomics Framework

et al. 2019

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Paracoccidioidomycosis (PCM) is the most prevalent endemic mycosis in Latin America. The disease is caused by fungi of the genus Paracoccidioides and mainly affects low-income rural workers after inhalation of fungal conidia suspended in the air. The current arsenal of chemotherapeutic agents requires long-term administration protocols. In addition, chemotherapy is related to a significantly increased frequency of disease relapse, high toxicity, and incomplete elimination of the fungus. Due to the limitations of current anti-PCM drugs, we developed a computational drug repurposing-chemogenomics approach to identify approved drugs or drug candidates in clinical trials with anti-PCM activity. In contrast to the one-drug-one-target paradigm, our chemogenomics approach attempts to predict interactions between drugs, and Paracoccidioides protein targets. To achieve this goal, we designed a workflow with the following steps: (a) compilation and preparation of Paracoccidioides spp. genome data; (b) identification of orthologous proteins among the isolates; (c) identification of homologous proteins in publicly available drug-target databases; (d) selection of Paracoccidioides essential targets using validated genes from Saccharomyces cerevisiae ; (e) homology modeling and molecular docking studies; and (f) experimental validation of selected candidates. We prioritized 14 compounds. Two antineoplastic drug candidates (vistusertib and BGT-226) predicted to be inhibitors of phosphatidylinositol 3-kinase TOR2 showed antifungal activity at low micromolar concentrations (<10 μM). Four antifungal azole drugs (bifonazole, luliconazole, butoconazole, and sertaconazole) showed antifungal activity at low nanomolar concentrations, validating our methodology. The results suggest our strategy for predicting new anti-PCM drugs is useful. Finally, we could recommend hit-to-lead optimization studies to improve potency and selectivity, as well as pharmaceutical formulations to improve oral bioavailability of the antifungal azoles identified.

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“…A CIM variou de 2 a 16 μg/mL (P. brasiliensis) e entre 16 a 32 μg/mL (P. lutzii). Estudos recentes descrevem outros candidatos selecionados por métodos in silico com atividade antifúngica semelhante (BUENO et al, 2019;CAPOCI et al, 2019;Rodrigues-Vendramini et al, 2019;SILVA et al, 2018). Apesar da CIM ser diferente da concentração fungicida mínima foi possível determinar a concentração capaz de erradicar o crescimento fúngico, que variou de 4 a 128 μg/mL.…”

Section: Corismato Sintase Para Novas Terapias In Vitrounclassified

Profissionais De Saúde E Participação Popular: Políticas Públicas E Tomadas De Decisões Em Saúde

Santos¹,

Santos²,

Santos³

et al. 2020

Estudos Em Ciências Da Saúde

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Todo o conteúdo deste livro está licenciado sob uma Licença de Atribuição Creative Commons. Atribuição 4.0 Internacional (CC BY 4.0). O conteúdo dos artigos e seus dados em sua forma, correção e confiabilidade são de responsabilidade exclusiva dos autores. Permitido o download da obra e o compartilhamento desde que sejam atribuídos créditos aos autores, mas sem a possibilidade de alterá-la de nenhuma forma ou utilizá-la para fins comerciais.

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Computer-aided identification of novel anti-paracoccidioidomycosis compounds

Cited by 15 publications

References 35 publications

Antifungal activity of two oxadiazole compounds for the paracoccidioidomycosis treatment

Antifungal activity of two oxadiazole compounds for the paracoccidioidomycosis treatment

Drug Repurposing for Paracoccidioidomycosis Through a Computational Chemogenomics Framework

Profissionais De Saúde E Participação Popular: Políticas Públicas E Tomadas De Decisões Em Saúde

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