Molecular docking to Toxoplasma gondii thymidylate synthase-dihydrofolate reductase and efficacy of raltitrexed in infected mice

Reis, Michelle de Paula; Lima, Daniely Alves de; Pauli, Karoline Bach; Andreotti, Carlos Eduardo Linhares; Moraes, André Luiz Soares de; Gonçalves, Daniela Dib; Navarro, Italmar Teodorico; Bueno, Paulo Sérgio Alves; Seixas, Flávio Augusto Vicente; Gasparotto, Arquimedes; Lourenço, Emerson Luiz Botelho

doi:10.1007/s00436-018-5835-5

Cited by 2 publications

(1 citation statement)

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“…T. gondii has a number of viable targets that can be inhibited by several drugs [ 39 , 40 ]. Thymidylate synthase-dihydrofolate reductase (TS-DHFR) was selected as a target for drugs that can eradicate this parasite [ 41 , 42 , 43 ] and 1UE ligand (the co-crystalized ligand inside active site) was chosen as a positive control compound. According to what was previously published, we found that there is a direct relationship between the inhibition of cyclin dependent kinase 2 (CDK2) and flavonoids in cancer therapy [ 44 , 45 , 46 , 47 ].…”

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confidence: 99%

Evaluation of Zamia floridana A. DC. Leaves and Its Isolated Secondary Metabolites as Natural Anti-Toxoplasma and Anti-Cancer Agents Using In Vitro and In Silico Studies

et al. 2022

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Toxoplasmosis and cancer are life-threatening diseases with worldwide distribution. However, currently used chemosynthetic treatments are not devoid of their own intrinsic problems. Natural metabolites are gaining attention due to their lower side effects. In this study, we investigated for the first time Zamia floridana leaves extract and its different fractions for their toxoplasmocidal activity, using Virulent RH Toxoplasma gondii, and cytotoxic activity against MCF-7 and HCT-116 cancer cell lines using MTT assay. The n-butanol fraction was the most potent fraction against T. gondii with an EC50 of 7.16 ± 0.4 µg/mL compared to cotrimoxazole (4.18 ± 0.3 µg/mL). In addition, the n-BuOH fraction showed a significant cytotoxicity against MCF-7 and HCT-116 with IC50 of 12.33 ± 1.1 and 17.88 ± 1.4 µg/mL, respectively, compared to doxorubicin (4.17 ± 0.2 and 5.23 ± 0.3 µg/mL, respectively), with higher safety index against normal cell line (WISH). Therefore, the n-BuOH fraction was investigated for its phytochemicals using extensive chromatographic techniques, which led to the isolation of six compounds that were fully characterized using different spectroscopic techniques. Three biflavonoids (1, 2 and 4) in addition to two phenolic acid derivatives (3 and 5) and a flavonoid glycoside (6) were isolated. Compounds (1, 3, 5 and 6) were reported for the first time from Z. floridana. In silico docking studies for toxoplasmocidal and cytotoxic effects of these compounds revealed that compounds (1, 2, 4 and 6) have promising inhibition potential of either thymidylate synthase-dihydrofolate reductase (TS-DHFR) or cyclin dependent kinase 2 (CDK2) target proteins. This study is considered the first report of chemical and biological investigation of Z. floridana leaves.

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Section: Resultsmentioning

confidence: 99%

Evaluation of Zamia floridana A. DC. Leaves and Its Isolated Secondary Metabolites as Natural Anti-Toxoplasma and Anti-Cancer Agents Using In Vitro and In Silico Studies

et al. 2022

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The Broad-Spectrum Antitrypanosomal Inhibitory Efficiency of the Antimetabolite/Anticancer Drug Raltitrexed

Kandeel

Suganuma

2022

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Raltitrexed is a classical antifolate drug with antimetabolite and anticancer properties. In this research, we provide its detailed antitrypanosomal inhibition against six Trypanosoma species and investigate its potential mode of action. Molecular dynamics (MD) simulations and in silico analyses were used to track the binding strength and stability. Raltitrexed showed broad-spectrum trypanocidal actions against Trypanosoma brucei brucei GUTat3.1, T. b. rhodesiense IL1501, T. b. gambiense IL1922, T. evansi Tansui, T. equiperdum IVM-t1 and T. congolense IL3000. The estimated IC50 was found to be in the range of 5.18–24.13 µg/mL, indicating inhibition of Trypanosoma in the low micromolar range. Although the co-crystallized ligand had robust hydrogen bonding and lipophilic characteristics, its docking score was only −4.6 compared to raltitrexed’s −7.78, indicating strong binding with T. brucei dihydrofolate reductase-thymidylate synthase (TbDHFR-TS). MD simulations support the strong binding of raltitrexed with TbDHFR-TS evidenced by low root mean square deviation (RMSD), low residues fluctuations, a tight radius of gyration (ROG) and an average of 3.38 ± 1.3 hydrogen bonds during 50 ns MD simulation. The prospective extended spectrum of raltitrexed against Trypanosoma species grants further research for the synthesis of raltitrexed derivatives and repurposing against other protozoa.

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Molecular docking to Toxoplasma gondii thymidylate synthase-dihydrofolate reductase and efficacy of raltitrexed in infected mice

Cited by 2 publications

References 22 publications

Evaluation of Zamia floridana A. DC. Leaves and Its Isolated Secondary Metabolites as Natural Anti-Toxoplasma and Anti-Cancer Agents Using In Vitro and In Silico Studies

Evaluation of Zamia floridana A. DC. Leaves and Its Isolated Secondary Metabolites as Natural Anti-Toxoplasma and Anti-Cancer Agents Using In Vitro and In Silico Studies

The Broad-Spectrum Antitrypanosomal Inhibitory Efficiency of the Antimetabolite/Anticancer Drug Raltitrexed

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